CA1303991C - Composition and method for delivering a steroid active ingredient - Google Patents
Composition and method for delivering a steroid active ingredientInfo
- Publication number
- CA1303991C CA1303991C CA000533503A CA533503A CA1303991C CA 1303991 C CA1303991 C CA 1303991C CA 000533503 A CA000533503 A CA 000533503A CA 533503 A CA533503 A CA 533503A CA 1303991 C CA1303991 C CA 1303991C
- Authority
- CA
- Canada
- Prior art keywords
- composition
- active ingredient
- bead
- network
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Abstract
PATENT
COMPOSITION AND METHOD FOR DELIVERING A
STEROID ACTIVE INGREDIENT
ABSTRACT OF THE DISCLOSURE
Delivery vehicle comprising a polymeric bead hav-ing a network of pores with a solution of an active in-gredient absorbed within the network is provided for use with or without a medium in a method to provide controlled release of the active ingredient useful for topical therapeutic use. The network of pores is sub-stantially noncollapsible upon removal of the solution.
COMPOSITION AND METHOD FOR DELIVERING A
STEROID ACTIVE INGREDIENT
ABSTRACT OF THE DISCLOSURE
Delivery vehicle comprising a polymeric bead hav-ing a network of pores with a solution of an active in-gredient absorbed within the network is provided for use with or without a medium in a method to provide controlled release of the active ingredient useful for topical therapeutic use. The network of pores is sub-stantially noncollapsible upon removal of the solution.
Description
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PAT~NT
COMPOSITION ~ND M~THO~ FOP~
S ~LIVERIN~ A ~E~ID ACTIVE I~GREDIE~
~AC~GROUN~ OT ~E INVEN~ION
~he f~ eld o~ the presen~ in~ention relate~ gener ally to time re~ e deli~ry o~ a ~t~rold actlve ~n-gredien~, and ln p~r~cular a corti~ost roid activ~
~redien~ u~e~ul as, ~o~ axample, an ant~-ln1ammatory ag~nt .
In order ~o maxlmi2e th~ bene~it o~ su~h appli~a~
t~on, the vehis~ hould allGw dellvery ~o and ab~orp~
tion through the 3kin ~ur~ace to which i1: i3 appli~d.
Additionally, lt would be pre~rabl~ t:s provlde a tlm~
r~le~e mecl~nism ~or ~beorp~ion o~ the activ~ in-3redi-~n~.
Ther~ are a wlde v~riety o~ corltrolLed release products prs~ntly be~ ng utllized ln numerou~ appll~a ~
~ion~, ln~ludin~ pharmaceutical ~ ag:rlcultur~1 and vet-erin~y ~pplication~,, Generally ~peaking, an ~ativ~
lngredlellt i~ relea~ed ove~ tim~. ~h~ activ~ in~r~
ent may be contalned in a v~rlety o~ med~a, ~u~h ooa~ed partial~ (e.g. ~phere, ~ggregat~, mult~ple c~ating or pill), ~olid solu~ion~ (~.g. b~adl~ ilm, bandage or eube), ~ompc~ lon~ g, ~phere, t~let, plll8 or ~rlp~, ~ont~ rs ~. g. c~p~ule , br~a~cabl~
ampula or c~pilla~y~, ~nd ::ombirlation~ ~e. g. in a licauid, in a aap~ul~ or ln a plll).
~ icroenca1?sulatlol~ i3 th0 mo~t common prwe~ for preparing ~ tlme relea~a deliv~ry vf3hicle. ~ner~lly ~p~king~ ~nioroenc~p~ula~iorl utilt z~ a c:oatlng to ~on~
taln th~ activ~ gr~dl~n~ whlck~ hen r~lea~ed by ~upt~lre ox di~olution o~ th~ ao.t~ng~ Al~r~atlv~ly,, . ~
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the coating or membr~ne may be 6emi-perme~ble o~ p~rou~
to ~llow th~3 ~çtlve ingr~ t to di~u e ou~ o~ th~
mi~roencap~ul~ .
United States Pat~nt No~ 4,322,311 ~escribe3 an encap3ula~ion techni~ue for produ~ing 6emi~p~rme~ble ox ~ontrolled poro31ty mlcrocap~ulqs, An ~ctlv~ ingreal-ent and ~ monomer in a ~lrst olu~ion are emulslfled ln a hydrophoblc solvent. A monome~r complemelltary to the ~irst monom~r which 18 ~oluble in the hydrophob~c 501 Yent i~ added to the emulalon to initiate lnterfaclal polymerizatic~n about the ~aeou dropletS. During h~
~our~e o~ react~on~ the af~lnl~y o~ the contlnuou~
phase for ~he fl~ monomer iS t~aried by adding a sol-v~n~ to ~he con~lnuous phase to vary 1~ polarlty.
Thi~ promot~ diffu ion into the c~on~inuous ~ha~e re-sul~lng in a poro~ membr~ne. Sin~e th~ patent de-s~ribes th2 u3e o~ an amine monomer, ~ome amine monomer may ~emain enc:apsulated within the mic:rocapsul~.
Another ~ncapsulatlon ~ehnlque 1~ desoribed ~n Uni~ed S ~es Patent No. 4,444,~99 wh~rein mirlut~ cap~
3ules are m~nufa~tuxed er rnaB~e. ~he proce~ u~iîiæeo poly~ondensation o~ m~lamina with formaldehyd~ or in 9itU polymerlz~tlon of me~ylol meLamlne or ~tet~lfled m~thylol m~la~in~, or a low mol~ular w~ight polym0r ~5 ther~of, in an ~queou~ vebLcle and ~ch~ reaction i~ con-duct~d in th~ pr~nc~ of polyel~ctrolyt~ ma~erl~l And c~rtain salt~ oweve~ this proc:a~s will typi~ally leave some ro~idu~ o~ ~ormald~hyd~ which may po~a a health problem, Ot~er ex~mple~ ol~ encap~ula~ion techniqu~ ln-clud~, ~y way ~ exa~nple only, tJnited S~ate~ Pat~nt Numb~r~s 4,324,6~3, 4,353,809, 4~353,Ba8~ 4~353~962) 4,391,909, ~,396,670~ 4,407,957~ 4,43~,4a~, and 4,4~4,~71. T~o microGaE;~ule~ prc~duced by the0e ty~
o~ proc~e~ will typl.~ally p~ llmi~d mech~nioal ~tr~ngth and ~111 rele~2s~ all o~ ~hea ~ctive lngr~d~n~c~
a~ on~ th~3 m~mbran~ i8 rup~uread, ~h~ llmlt~d ,, = ~, ., ~l3~J3~
mechanical sta~ility can create problems with incorpo-rating the microcapsules into a medium and will also limit the shelf life of these delivery vehicles. In addition, the microcapsules will typically contain re-active groups which may create problems of chemicalstabilityO
Another delivery vehicle for an active ingredient is described in United States Patent No. 3,985,298 which utilizes a process to impregnate an active ingre-dient into and within a cellulosic polymer-liquid com-posite material as a part of or all of the liquidphase. The active ingredient is released from the gel matrix which shrinks or collapses as the active ingre-dient is removed. The gel structure is not mechanical-ly strong and therefore it suffers some of the mechani-cal problems associated with microspheres~
A number of problems have been encountered in theformulation of corticosteroid medicinal agents using delivery vehicles in the prior art. For example, in order to maximize topical corticosteroid penetration of, e.g., fluocinolone acetonide, the corticosteroid is initially dissolved in a co-solvent such as propylene glycol. This solution is then dispersed in, for exam ple, a primarily aqueous vehicle such as oil-in-water emulsion creams or lotions. Unfortunately, the initial solution of steroid in propylene glycol becomes diluted into the aqueous base, in which it miscible, and the steroid precipitates, resulting in a suspension of cor-ticosteroid which is less favorable for percut~neous absorption than a solution of corticosteroid. It would therefore be desirable to dissolve the steroid in a water immiscible solvent/penetrant, such as Azone. Un-fortunately, Azone may accentuate skin reactions asso-ciated with some formulation excipients, as for example the skin irritation associated with propylene glycol and cer~ain preservatives. In addition, this approach would require emulsification of the Azone solution 1~
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using other lipophilic materials and emulsifiers. How-ever, these are contraindicated since it has been ob-served that large amounts of lipophilic agents such as petrolatum, mineral oil, high molecular weight poly-ethylene glycols, or esters of mono- and dicarboxylic acids, e.g., isopropyl myristrate, diethyl sebacate and diisopropyl adipate, should be avoided since they ap-pear to dissolve Azone and suppress its penetration-enhancing activity.
In addition, when petrolatum or other lipophilic vehicles are used as topical corticosteroid delivery vehicles, other problems exist. A typical cortico-steroid ointment consists of a solution of steroid in propylene glycol and/or propylene carbonate which is dispersed in immiscible petrolatum with the aid of emulsifying agents such as Amerchol CAB (a mixture of sterols and higher alcohols). In thi~ case, the steroid solution is only quasi~emulsified and separates out on standing, resulting in a non-homogenous product.
This separation drastically interferes with the uni-formity of the medication. Furthermore, the use ofAzone as a penetration enhancer is precluded from use as a solvent for steroids and other functional drugs for forming ointm~nts in lipophilic vehicles because, as noted above, such vehicles may suppress the pene-tration-enhancing activity of Azone.
The use of encapsulation in connection with corti-costeroid agents requires a shell which must be dis-solved or ruptured toi release the contained cortico-steroid. The use of such an encapsulated orm of medi-cation may present the problems of poor mechanical stability or reduced shelf life. Furthermore, time-release control of the contained corticosteroid may be difficult to ohtain because full release occurs upon xupture or dissolution of the encapsulant.
Accordingly, there exists a need for an economical time-release delivery vehicle with high mechanical ,~,.~.
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~tr~n~th u$eful in a ccntroll~d-relaas~ application ~ox dellvering ~tç3roid a~tive agents, as f~r example cor~ico~te~olds .
SUM~ARY O~ TE~E INVEN~ION
The inven~lon rel~t~ to a m~thod ~or delive~ing a steroid ~ctive ir~r~di~n~, and in par icular ~ cortico-3terold actlve ing~edient, to a ~kin surface by con-troll~d tlme-r~leae~. In another a~pe~ o~ the present inven~ion, a composition o~ matte~ u e~ul ln the m~thod of ~ha ln~an~ in~en~ion i9 di~clos~d.
In 'che lnstant in:ventiQn, ~ d~ irory veh~ole aom~
pr~ sed of a pre~orm~d polym2ric b~ad ha~ing a networ~
o pores with a 30Lu~ion o~ ~he a~itte ingredient held wlthin the network is Utili~3d tc~ pr~vid~ ~ ~ontrolled tim~ rel~a e o~ th~ ~cklv~ lng~edlent. P~ perc~ neo~
Absorp~ion e~hanaer, which lprovides increa~@~ thermo-dynamlc actlvi~y and pene~rabllity o~ t~e acti~e in~re-di~nt through the ~kin. ~ur~ace, m~y be us~d to fonn the aa~lve lngredt e~t ~olution. The d~ ery vehicle may be incorporated ln a ~dlum, 3uch a~ a gel, a ~ream, a lotion, an ointn~nt, a li~uid ~r the lik~, wh~ch may then be appli~d to a skin sur~a~. Th~ a~lu'cion ~ 9 r~-~5 le~Red ~rom ~-h~ network of por~ ov~ time~
A d~llvery ve}~icl~ ac~ording to the present inven-tlon has aontlnued mechanl~al ~t~blllt~ durin~ us~ aa comp~red to a micro~ncap~ulat0d or g~l d~liv~ry vehi~
ale, ~he network oi~ po~e~ o~ a b~ad ~ccor~lng tc~ ~he pre~eht inrerlti.on w~ ot ~e ~ubject ~o o~mt)t~ ~ho~lt which m~ght occur ~n pxlor rt dell~e~y ~ohi~l~s. In addi~on, ~he lncre~e~ mech~nic~ a~ility ~llow~
~eliv~3ry vahicl~ tc~ b~ ma~ufa~tured ~ proc~3~d and hantlqd und~r more ~ev~re ~ondition~, such i~L9 mech~ni-tirring, whi~h mi.ght oth~r~riaa rup~ur~ o~ d~ma~
~om~ prior a~ ~el o~ ml~oe~ap~ula~ed de1i~rery ~ehi~
. cl~. Thu~, a d~liv~ry vehlcl~ xdlng to th~ pr~-., ,.
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en~ ln~r~ntlon can eA~ily ba incorporat~d in certaln media in which lt would prove dl~ic~llk ~r ~n~rR Rxpen-~ive to incsrporat~ d~llvery vehicle~ o~ the prior ar~.
The l3e o~ t:he d~livery vshicl~ of th~ pr~senl:
invention allows the entrapment of a ~olution of 6ter-oid ln a ~olven~ ~uch a~, for example, Azon2 whlch can then r~adlly be di~pers~d in typical as~u~ous gel, lotion and cream formullations, a~ well as in l~pophlli¢
delivery ~ehi~le~. The entraptnent o~ Azonx in tl~
polymer beads ~ubs~anti~lly prev~n~ any allu~l~n o~
~h~ con~ined ~olution by contraindicated lipophilic materials, upon ev~poration or di~ipatior1 o~ ~he aqueou~ or lipophilic medlum, the bead~ remaln lntact ~nd ~he cont~insd sc)lution o~ act ~ ve agent and, for example, A20ne i~ ~elea8e~ in ~ hi~hly ~oncentrated manrler to tlle s!cin through conta~t pres3ur~, exuda~cion and capillary acti~n.
In contras~ to qua3i-emul3l. ~ied ~terold 801utlon3 formed in petrol~tu~ ~nd other lipophilic medii!L, th~
3u~pen~ion o~ th~ polymer bead3 o~ ~h~ pres~n~ inven ~ion i~ higl~ly ~t~ble ~nd doe~ no~ t~nd to separat~
from the delive~y medi~um ov~r tima. Thi3 r@~ult~ ln product wh~ch remalns unl~ormly dl~per~ed th~o~l~hout ~he deli~e~y medium an~ do~ not ~i3nd to agglomer~ or pool.
~urthermor0, a~ als~u~e~ ~hove, A~ne may accen-~uate ~kin ~e~ ne typically ~een with ~om~ ~ormula-tion ex~ipi13nt~. By formulating produc:t w~ th Azone entrapped in ~he be~d, probl0m~ such a~ irritation ~n-hancement may ~ redu~ed.
When a dç~livexy v~hicle a~cording ~o ~h~ p~e~ent lnvantlon 1~ polymeri2~d ~rom ~tyrene and divinylberl-z~ne, ~h~ dell~rery vshl~l~ will pos~ee~ grea~r chemi~
~al ~t~blllty o~er p~e~ious d~liv0ry vehicl~e bQ~au~
th~3 sty~r~n~a divlnyll:~nzen~ p~ ia }~at will not con-tain r~ac~clva group~ and wlll ~oa~81~1; ¢g~n~lally of o~
hydroc~rbon b~ckbone with b~nzen~ rlng~ cau~e th~
3~
styrene divinyl~nzen~ polymeri~ b~ad doe~ not ~on~ain reactive group~, th~ bead will no~ reAdlly und0~go un-wan~ed r~ations, it will be atable over a v~ry ~ld~ pH
range, it wlll reslst moaerate oxid~ion and reductlorl, lt ~ill b~ s~able to h~gher te~nperatuxe~, it will no~
b~ ~ub~ect to Atta~k b~ moi~ture, and it wlll have a longer h~lf life. In ~ddlt~on, in contra~t to som~
prlor ~ct delivery vehicl~, a ~tyren~ d1vinylbenzen~
polym~ri~ bead of the p~e~ent inven~ion doe~ r~ot con-~a~n ~ny reat:tive~ group~ or polym~rlc s~ru¢tu~e whic~
may cauae a problem oP toxici~y, irritation or the like when applied ~opically to skls~.
Ano~-he~ advant~ge of a d~liv~ry vGahiale prepared in accordan~e wi~h ~he p~&~ent lnv~ntion i~ the ~ub-~tantial abs~nc~ o~ un~a~ted monomer d Thu~, ~ n a micoen~ap~ulation deli,very v~hi~lQ it may be dif~i~ult ~o ~emove unrea~ted monomer becau3e 1~ mi~ht beaom~
encapsul&ted along with the~ active ingredient in~ide o~
th~ membrane, Thl~ pr~blem iB ~pe~ially ~eute i~ ~ome prior a~t delivery veh,~les which l~tlllze ur~a-formal~
d~hyde microcap8ule~ wpl~h can create potential health problem~ .
Acoordinglyt it i~ ~ prinl~ry obje~t o~ the pre~en~
invention to provide a; dellve~y ~rehi~le ~or delivering an active ingredlent~ cont~olled time rele~q ov~r A
perlod of time to a skin sur~a~:a. Thi~ and ~urther obje~ts ant advant~e~l of the pre~ent intvention will becs~m~ apparen~c to ona o~ ordln~ry ~klll in the a~ in connaation with th3 d~ d de~crip~ion o~ ~h~ pre-ferr~d em~odlm~nt3 B13t forth below~
In a~ord~nce wit~ the presen~ in~en~ion, ~n 3 a~tiv~ lngr~dlen~ ~olul~ on 1~ 8u~pendsd in a ne . work o~
pore4 o~ a po~ous polyfneric bead whi~h i~ ~1 p~r~ed in a v~hi~le ~ubatan~all~ ible wi~h h~ ~olution~
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A percutaneou~ ~bso~ption enharlcer will typ~cally he u~ed a3 a ~olvent ~or th~ active ingredi~nt.
A porou~ polymeric bead a~ordln~ ~o th~ pre~ent inventiorl can b~ pr~pa~ed 4y pol~merizing on~ or more rronomer~ ~y ~ fre~ radlaal suspenston polym~rizatiorl proces~. A monom~r or pair of comonomer~ i~ dis~olv~d in an in~rt porogen ~o form a ~olutlon whi~h i~ sus-psnded in a pha~e or 301V~lnt imcolopa~ible wlth the solu~lon .
An @xample of such a ph~ or ~olvent mlyht be water with 3tabil~zlng additive60 Af~r th~ 301ution ls unpended ln the pha3e, the olution . r~d phase are agit~ted ~o forrn a plurall~ of dropl~?ts o olu~ior~
suspended ln the pha~e. A~r th~3 forma ion of ~he lS plurality of droplet~, the monomer or monomer~ in the plurality of drDplets are activat~d to initiate polymerization rea~tion Ln whiah one ox morq monomer~
ar~3 polymeriz~d ~o fc~rm porous bead~ ha~ing a network of pore~ with ~he po~ogen held wlthin th~ network ~f pore~, The act~vatl~n may ba triggered by an lnltlator which is soluble in the morlomer ~olutlon, ~lternativ~ly, ac~ivation may be t~iggered by ~n energy ~ourc~ ~u~h a;
radia~cion. ~he inert poros~n w~ erve as an intern~l dlluen~ durln~ polymerl~atlon to in~roduce ~he de~lr~d ~5 spong~-llke macroporou 'cr~ ure or networX o;E pores into the ~ini ~h~d polym~ be~d ~ Tha in~rt porogen should not r~a~t w~h th~ monom~r pr~nt durlng polyme~izAtion or lnhibi~ th~ polymeriza~i~n. Th~
polym~ric ba~d may or m~y not 6w~ n th~ in~rt porogen/ Af~r th~ ~ormation o~ ~he pO~ polymerl~
~e~do, tl~e polymerl~ be~d~ are 3eparat~d ~rom th~ pha~e and subj~cted to on~ o~ n~ore pll~ifl~tior~ s~ep~, ~uch a~ w~h~ng, ~o ramo~re any unraa t~d monomer or lmpurlty ~rom the bead~, Porou~ ~olymerle beacl~ u~e~ul in the pre~nt in-vea~tlon Ga~ be Earepar~ed ut~ ing ~h~ gen~ral d~crip-tlon and pro ::edure~ ~t for~h ln Un~d Stateo P~tent ~3~
4,690,825, i~sued in Septe~ber 1987. ~owever, unles~ the active ingredient solution can serve as a porogen during the polymerization of the polymeric bead~, then the porogen mu~t be removed and replaced by said solution. Although these extra steps are not as desirable as using the solution as the porgen, satisfactory porous polymeric beads can still be obtained if the network of pores of said beads is substantially non-collapsible after removal of the porogen and remains substantially non-collapsible upon removal of the active ingredient.
The polymeric beads used in the present invention can be designed so as to control porosity and the particle diameter of the beads, which may be considered substantially spherical. Under identical poIymerization conditions, the porosity can be increased by increasing the ca~culated or t~heoretical cro~s-linking density or by increasing the porogen concentration in the solution. An increase in porosity will increase the surface area of the bead and hence the weight percent of the porgen which can be held within the bead. To decrease the particle diamete under identical poly-merization conditions, the agitation or the concentration of dispersion agents in the phase should be increased. By controlling the porosity and the particle diameter of the bead, a delivery vehicle suitable for use in the method of the present invention can be obtained. Generally speaking, it has been found that it is preferable for the bead to have a diameter from about 10 microns to about 100 microns, and have a calculated cross-linking in exces~ of about 10%. A
cross-linking of approximately 20% to 50% is preferred, with the range of approximately 25% to 30% being especially preferred. The pores in the beads of the present invention will typically range in diameter from approximately 10 angstrom~ to approximately 500 ang-13~P3~
stroms, ~he ~olution of th2 active inS~r~dient ~h~uld compri~ betwsen appro~clm~tely 5% to ~pproxlm~tely RO~
of the total w~ight o~ t~e compoQi~lon ~r d~livery Y~h~cl~ oompri~in~ the polymerl~ ~ead and said ~olu-~lonO
~o dls~tngul~h whether a porous polymeric ~ead posseq~es suffic~ient mechanl~al str~n~t~ to be u~ed a delivery vehi~le ~o:c providing con~rol}ed time-release o~ the ~olutloal aont~ining ~he ~tiv~ ingredi-1~ en~, the çompo~3ition aan be Qub~eated to a wettln~
~e~t. I~ the GompoRi~on }la~ a ~al~ ted. cro~-link-lng den31ty an~ a solukion con~e~ntration 3uch hat sub~
~tantially all of ~he ~ollltion ~il b~ r:ela~d from tbe network of pores when the bead i~ placed ln a ~ol-ven1:, ln whl~ thR ~olution i~ solubl~, ~or a su~fl-~
cient leng~h of tlm~ t~ we~ ~he b~ad, ~h~n ~he ~ompo~
tlon can ~ ed irl ths method o~ the pre~ant inven-tiorl .
A wetting test carl be perform~d by w~ighing a d.ry ~ample or materl~l ~o b~ ~e~ed contAin~ ng an origin~l amount o~ ~olutlon ~onka ~ ning the ~ctiv~ ingr~d~en~ .
The d~y sample i~ n Inix~d with a ~lv~nt in whlch the ~olution i~ soluble to ~orm ~ wet ~ample. Th~ w~t ~ample i~ ~h¢n Agl tat~d ~or a su~ici~3n~ lerlgth of tim~
to wet th~3 bead 1~ th~ dry ~mple 1~ eomp~is~d or~ ~
delivery vehlQle ~c~ording to thc pre~ant inv~rltion.
mount o~ ~olution relea~ed in~o ~ha ~olv~nt i8 then d~t~rmlne~, ~he amount o~ ~olu~lo~ rele~d i~
t~e ~olvent will b~ su1~stantially ~he ~ame a~ th~
original amoun~ of ~olution i~ the dry s~m~l~ consl~ked es~ent~ally of the d~liv~ry l~ehial~ wh~re~3 the re-lea~ad amount wlll be ~ub~tantially les~ ~h~n ~h~
o~lglnal ano~lnt ii~ the d~y ~mpl~ ~on~ained a ub~tan-tial amount o~ a g~l product o~ a n~icroe~ poul~ e~
p~oduc~. If ~h~ 301u~1On con~alnin~ ~he ~cti~ ~n~re~
dlen~ i8 not ~ch-3 poro~3n, then a w~lng t~t aan b~
uYed to ~onfirm tha~ ~he poro~en ~ no~ been en~ap~u-~L3~3~
1~
l~ad. Th~ conc~ntra'c~on of the A~ive ingredi~n~ ln ~uch a ~eli~ery v~hi~le ~an be d~ermln~d ~y ~ solvent w~tting ~ rollowed by an a~Ay, ~ h a~ ~ gr~vi-metrlc or W a~ay.
To utlllze a delL~ery vehicle in ~cord~nce wlth t}l~ me~hod o~ the presen~ lnv~n~ion, the delivery ~eh~cle ma~ be m~xsd ~ith a d~liv~ry medium t~ form a m1 xture which 1~ applled to a skin ~lr~ce . The ~olu-tlon of the ac~ivo in~redient i8 then releA~ rom the n~tworlc o~ pore~ by ~ $o~c:c or ~ergy. Thu~, ~y way o~
ex~mple only, ~h~ controlled time release migh~ oc~ur through dif~l~ion~ Be~auae th~ solution iB held Iprl-marily by ~bsorpt9 on) wlthin th~ net~o~c of pores o~
the pol~m~ric be~d~, ~h~a çon~entration of the ~olutl4n in tha medium will tend to be ~airly uniform and will not b~ a~ likely to agglom~rat~ or pool as 1~ the 901u ~ion had ~lmply been dlsperse~ within ~he medium. P~
the sol~tior~ i8 delivered to the skin $ur~ace, the per~
cu~aneou3 ab~orptlon enhan~ ol~ent ~ill protnote maxilnum t~e~modynamia a~tivity and penetrabili y ol~ th~
ac~ive lngred~ent, Ex~mplee oi~ pO3 ibla percutan~oua ~b~orptiorl enhancers inoludq p~op~lene ~lycol and p~o-pyl~ne c~otl~t~ which are use:Eul with corti~oateroid~l Numerous o~her pos31hl~ percut~neo~l~ ab~s~ption enh~nc-ere ar~ well-known ~o ona 8klll2tl ln the art ~nd migh~
in~luae, by ~ y or~ ~x~mpla only, dialky~ul~oxldQ~
~ving up to 22 carbons ln e~ch Al~cyl ~ro~lp, ~ ~ g a, dimethyl~ul~c~xlder dime~hylform~mida, ~im~athylac~ca mldo, dil~opxopyl a~ip~t~ opropyl myri~tat~ r~
~dro~urxn, tetrahydroi~ux~uryl ~ ohol, glycerol ?
~-me~hyl~2-pyrrolidon~ ~n~ ~ ~roduct avallabl~ under the tradem~rk ~ZONE ~l-dod~aylhex~hyd~o~2~aæ~pi~-2-one).
A number o~ dclivery ~edla may b~ u~d ln aon~una-~lon with ~h~ polymer bead d~livery ~e~tcle o~ th~
pres~nt lnventlon, and m~y b~ ~or~ulat~d u~ing materials and ~echnlq~e~ w~ known ~n ~h~ art, A
~ 33~
patrolatumtpolysilox~n~ba~ed d~livexy medium appropri-ate fo~ u~è ~,erein i~ d~cr1b~d in U.S~ P~tent No, 4,017,615. ~he d~llve~y ~edi~m ~hould b~ ~ubstantlally lmml~clble with th~ ~olutio~ contalning ~h~ active 5 ingredient, Pet~ola~um compound~ ranging in visco~ity from mineral oil to palr~f~ln waxe~ ar~ ~uit~bl~ m~dia, ~lt~ ~ p~raffin ~ompound h~ing approximately the conslstenc~ of petrolatum N~ ~petroleum jelly~ being e~peclally pre~rred as an oln~m~n~ ba~e. Poly~ilox~ne aompounds (also k~own A~ silico~e~ having appropriat~
vi~co~i~y charaaterlstic~ ~approxlma~ely ~O5 to 106 aen~ okes) a~e al30 sui~bl~ for U5~ as deliv6~ry media component~. Other ma~erial~ Xnown ~o the art, incl~di~g without excluslon adjuvan~s ~uch a~ beeswax, apermaaetl, paraffln waxes, and fatty acid~, alcohol~
~nd amldes having 10 to 22 carbon a~oms~, 3urfaatant~
thickeners, preservatlve~ hibi~ors and emul~i~ier3 may b~ ded within th~ deliv~ry m~dium usad har~in~
~he polym~r ~ead delivery vehi~le of th~ pre~e~
PAT~NT
COMPOSITION ~ND M~THO~ FOP~
S ~LIVERIN~ A ~E~ID ACTIVE I~GREDIE~
~AC~GROUN~ OT ~E INVEN~ION
~he f~ eld o~ the presen~ in~ention relate~ gener ally to time re~ e deli~ry o~ a ~t~rold actlve ~n-gredien~, and ln p~r~cular a corti~ost roid activ~
~redien~ u~e~ul as, ~o~ axample, an ant~-ln1ammatory ag~nt .
In order ~o maxlmi2e th~ bene~it o~ su~h appli~a~
t~on, the vehis~ hould allGw dellvery ~o and ab~orp~
tion through the 3kin ~ur~ace to which i1: i3 appli~d.
Additionally, lt would be pre~rabl~ t:s provlde a tlm~
r~le~e mecl~nism ~or ~beorp~ion o~ the activ~ in-3redi-~n~.
Ther~ are a wlde v~riety o~ corltrolLed release products prs~ntly be~ ng utllized ln numerou~ appll~a ~
~ion~, ln~ludin~ pharmaceutical ~ ag:rlcultur~1 and vet-erin~y ~pplication~,, Generally ~peaking, an ~ativ~
lngredlellt i~ relea~ed ove~ tim~. ~h~ activ~ in~r~
ent may be contalned in a v~rlety o~ med~a, ~u~h ooa~ed partial~ (e.g. ~phere, ~ggregat~, mult~ple c~ating or pill), ~olid solu~ion~ (~.g. b~adl~ ilm, bandage or eube), ~ompc~ lon~ g, ~phere, t~let, plll8 or ~rlp~, ~ont~ rs ~. g. c~p~ule , br~a~cabl~
ampula or c~pilla~y~, ~nd ::ombirlation~ ~e. g. in a licauid, in a aap~ul~ or ln a plll).
~ icroenca1?sulatlol~ i3 th0 mo~t common prwe~ for preparing ~ tlme relea~a deliv~ry vf3hicle. ~ner~lly ~p~king~ ~nioroenc~p~ula~iorl utilt z~ a c:oatlng to ~on~
taln th~ activ~ gr~dl~n~ whlck~ hen r~lea~ed by ~upt~lre ox di~olution o~ th~ ao.t~ng~ Al~r~atlv~ly,, . ~
, ~ -, `
3$,~
the coating or membr~ne may be 6emi-perme~ble o~ p~rou~
to ~llow th~3 ~çtlve ingr~ t to di~u e ou~ o~ th~
mi~roencap~ul~ .
United States Pat~nt No~ 4,322,311 ~escribe3 an encap3ula~ion techni~ue for produ~ing 6emi~p~rme~ble ox ~ontrolled poro31ty mlcrocap~ulqs, An ~ctlv~ ingreal-ent and ~ monomer in a ~lrst olu~ion are emulslfled ln a hydrophoblc solvent. A monome~r complemelltary to the ~irst monom~r which 18 ~oluble in the hydrophob~c 501 Yent i~ added to the emulalon to initiate lnterfaclal polymerizatic~n about the ~aeou dropletS. During h~
~our~e o~ react~on~ the af~lnl~y o~ the contlnuou~
phase for ~he fl~ monomer iS t~aried by adding a sol-v~n~ to ~he con~lnuous phase to vary 1~ polarlty.
Thi~ promot~ diffu ion into the c~on~inuous ~ha~e re-sul~lng in a poro~ membr~ne. Sin~e th~ patent de-s~ribes th2 u3e o~ an amine monomer, ~ome amine monomer may ~emain enc:apsulated within the mic:rocapsul~.
Another ~ncapsulatlon ~ehnlque 1~ desoribed ~n Uni~ed S ~es Patent No. 4,444,~99 wh~rein mirlut~ cap~
3ules are m~nufa~tuxed er rnaB~e. ~he proce~ u~iîiæeo poly~ondensation o~ m~lamina with formaldehyd~ or in 9itU polymerlz~tlon of me~ylol meLamlne or ~tet~lfled m~thylol m~la~in~, or a low mol~ular w~ight polym0r ~5 ther~of, in an ~queou~ vebLcle and ~ch~ reaction i~ con-duct~d in th~ pr~nc~ of polyel~ctrolyt~ ma~erl~l And c~rtain salt~ oweve~ this proc:a~s will typi~ally leave some ro~idu~ o~ ~ormald~hyd~ which may po~a a health problem, Ot~er ex~mple~ ol~ encap~ula~ion techniqu~ ln-clud~, ~y way ~ exa~nple only, tJnited S~ate~ Pat~nt Numb~r~s 4,324,6~3, 4,353,809, 4~353,Ba8~ 4~353~962) 4,391,909, ~,396,670~ 4,407,957~ 4,43~,4a~, and 4,4~4,~71. T~o microGaE;~ule~ prc~duced by the0e ty~
o~ proc~e~ will typl.~ally p~ llmi~d mech~nioal ~tr~ngth and ~111 rele~2s~ all o~ ~hea ~ctive lngr~d~n~c~
a~ on~ th~3 m~mbran~ i8 rup~uread, ~h~ llmlt~d ,, = ~, ., ~l3~J3~
mechanical sta~ility can create problems with incorpo-rating the microcapsules into a medium and will also limit the shelf life of these delivery vehicles. In addition, the microcapsules will typically contain re-active groups which may create problems of chemicalstabilityO
Another delivery vehicle for an active ingredient is described in United States Patent No. 3,985,298 which utilizes a process to impregnate an active ingre-dient into and within a cellulosic polymer-liquid com-posite material as a part of or all of the liquidphase. The active ingredient is released from the gel matrix which shrinks or collapses as the active ingre-dient is removed. The gel structure is not mechanical-ly strong and therefore it suffers some of the mechani-cal problems associated with microspheres~
A number of problems have been encountered in theformulation of corticosteroid medicinal agents using delivery vehicles in the prior art. For example, in order to maximize topical corticosteroid penetration of, e.g., fluocinolone acetonide, the corticosteroid is initially dissolved in a co-solvent such as propylene glycol. This solution is then dispersed in, for exam ple, a primarily aqueous vehicle such as oil-in-water emulsion creams or lotions. Unfortunately, the initial solution of steroid in propylene glycol becomes diluted into the aqueous base, in which it miscible, and the steroid precipitates, resulting in a suspension of cor-ticosteroid which is less favorable for percut~neous absorption than a solution of corticosteroid. It would therefore be desirable to dissolve the steroid in a water immiscible solvent/penetrant, such as Azone. Un-fortunately, Azone may accentuate skin reactions asso-ciated with some formulation excipients, as for example the skin irritation associated with propylene glycol and cer~ain preservatives. In addition, this approach would require emulsification of the Azone solution 1~
.
~,; .
13~3~
using other lipophilic materials and emulsifiers. How-ever, these are contraindicated since it has been ob-served that large amounts of lipophilic agents such as petrolatum, mineral oil, high molecular weight poly-ethylene glycols, or esters of mono- and dicarboxylic acids, e.g., isopropyl myristrate, diethyl sebacate and diisopropyl adipate, should be avoided since they ap-pear to dissolve Azone and suppress its penetration-enhancing activity.
In addition, when petrolatum or other lipophilic vehicles are used as topical corticosteroid delivery vehicles, other problems exist. A typical cortico-steroid ointment consists of a solution of steroid in propylene glycol and/or propylene carbonate which is dispersed in immiscible petrolatum with the aid of emulsifying agents such as Amerchol CAB (a mixture of sterols and higher alcohols). In thi~ case, the steroid solution is only quasi~emulsified and separates out on standing, resulting in a non-homogenous product.
This separation drastically interferes with the uni-formity of the medication. Furthermore, the use ofAzone as a penetration enhancer is precluded from use as a solvent for steroids and other functional drugs for forming ointm~nts in lipophilic vehicles because, as noted above, such vehicles may suppress the pene-tration-enhancing activity of Azone.
The use of encapsulation in connection with corti-costeroid agents requires a shell which must be dis-solved or ruptured toi release the contained cortico-steroid. The use of such an encapsulated orm of medi-cation may present the problems of poor mechanical stability or reduced shelf life. Furthermore, time-release control of the contained corticosteroid may be difficult to ohtain because full release occurs upon xupture or dissolution of the encapsulant.
Accordingly, there exists a need for an economical time-release delivery vehicle with high mechanical ,~,.~.
c~
, :
.
-~ ~L3t~3~
~tr~n~th u$eful in a ccntroll~d-relaas~ application ~ox dellvering ~tç3roid a~tive agents, as f~r example cor~ico~te~olds .
SUM~ARY O~ TE~E INVEN~ION
The inven~lon rel~t~ to a m~thod ~or delive~ing a steroid ~ctive ir~r~di~n~, and in par icular ~ cortico-3terold actlve ing~edient, to a ~kin surface by con-troll~d tlme-r~leae~. In another a~pe~ o~ the present inven~ion, a composition o~ matte~ u e~ul ln the m~thod of ~ha ln~an~ in~en~ion i9 di~clos~d.
In 'che lnstant in:ventiQn, ~ d~ irory veh~ole aom~
pr~ sed of a pre~orm~d polym2ric b~ad ha~ing a networ~
o pores with a 30Lu~ion o~ ~he a~itte ingredient held wlthin the network is Utili~3d tc~ pr~vid~ ~ ~ontrolled tim~ rel~a e o~ th~ ~cklv~ lng~edlent. P~ perc~ neo~
Absorp~ion e~hanaer, which lprovides increa~@~ thermo-dynamlc actlvi~y and pene~rabllity o~ t~e acti~e in~re-di~nt through the ~kin. ~ur~ace, m~y be us~d to fonn the aa~lve lngredt e~t ~olution. The d~ ery vehicle may be incorporated ln a ~dlum, 3uch a~ a gel, a ~ream, a lotion, an ointn~nt, a li~uid ~r the lik~, wh~ch may then be appli~d to a skin sur~a~. Th~ a~lu'cion ~ 9 r~-~5 le~Red ~rom ~-h~ network of por~ ov~ time~
A d~llvery ve}~icl~ ac~ording to the present inven-tlon has aontlnued mechanl~al ~t~blllt~ durin~ us~ aa comp~red to a micro~ncap~ulat0d or g~l d~liv~ry vehi~
ale, ~he network oi~ po~e~ o~ a b~ad ~ccor~lng tc~ ~he pre~eht inrerlti.on w~ ot ~e ~ubject ~o o~mt)t~ ~ho~lt which m~ght occur ~n pxlor rt dell~e~y ~ohi~l~s. In addi~on, ~he lncre~e~ mech~nic~ a~ility ~llow~
~eliv~3ry vahicl~ tc~ b~ ma~ufa~tured ~ proc~3~d and hantlqd und~r more ~ev~re ~ondition~, such i~L9 mech~ni-tirring, whi~h mi.ght oth~r~riaa rup~ur~ o~ d~ma~
~om~ prior a~ ~el o~ ml~oe~ap~ula~ed de1i~rery ~ehi~
. cl~. Thu~, a d~liv~ry vehlcl~ xdlng to th~ pr~-., ,.
. .
~~ ~L3~3~
en~ ln~r~ntlon can eA~ily ba incorporat~d in certaln media in which lt would prove dl~ic~llk ~r ~n~rR Rxpen-~ive to incsrporat~ d~llvery vehicle~ o~ the prior ar~.
The l3e o~ t:he d~livery vshicl~ of th~ pr~senl:
invention allows the entrapment of a ~olution of 6ter-oid ln a ~olven~ ~uch a~, for example, Azon2 whlch can then r~adlly be di~pers~d in typical as~u~ous gel, lotion and cream formullations, a~ well as in l~pophlli¢
delivery ~ehi~le~. The entraptnent o~ Azonx in tl~
polymer beads ~ubs~anti~lly prev~n~ any allu~l~n o~
~h~ con~ined ~olution by contraindicated lipophilic materials, upon ev~poration or di~ipatior1 o~ ~he aqueou~ or lipophilic medlum, the bead~ remaln lntact ~nd ~he cont~insd sc)lution o~ act ~ ve agent and, for example, A20ne i~ ~elea8e~ in ~ hi~hly ~oncentrated manrler to tlle s!cin through conta~t pres3ur~, exuda~cion and capillary acti~n.
In contras~ to qua3i-emul3l. ~ied ~terold 801utlon3 formed in petrol~tu~ ~nd other lipophilic medii!L, th~
3u~pen~ion o~ th~ polymer bead3 o~ ~h~ pres~n~ inven ~ion i~ higl~ly ~t~ble ~nd doe~ no~ t~nd to separat~
from the delive~y medi~um ov~r tima. Thi3 r@~ult~ ln product wh~ch remalns unl~ormly dl~per~ed th~o~l~hout ~he deli~e~y medium an~ do~ not ~i3nd to agglomer~ or pool.
~urthermor0, a~ als~u~e~ ~hove, A~ne may accen-~uate ~kin ~e~ ne typically ~een with ~om~ ~ormula-tion ex~ipi13nt~. By formulating produc:t w~ th Azone entrapped in ~he be~d, probl0m~ such a~ irritation ~n-hancement may ~ redu~ed.
When a dç~livexy v~hicle a~cording ~o ~h~ p~e~ent lnvantlon 1~ polymeri2~d ~rom ~tyrene and divinylberl-z~ne, ~h~ dell~rery vshl~l~ will pos~ee~ grea~r chemi~
~al ~t~blllty o~er p~e~ious d~liv0ry vehicl~e bQ~au~
th~3 sty~r~n~a divlnyll:~nzen~ p~ ia }~at will not con-tain r~ac~clva group~ and wlll ~oa~81~1; ¢g~n~lally of o~
hydroc~rbon b~ckbone with b~nzen~ rlng~ cau~e th~
3~
styrene divinyl~nzen~ polymeri~ b~ad doe~ not ~on~ain reactive group~, th~ bead will no~ reAdlly und0~go un-wan~ed r~ations, it will be atable over a v~ry ~ld~ pH
range, it wlll reslst moaerate oxid~ion and reductlorl, lt ~ill b~ s~able to h~gher te~nperatuxe~, it will no~
b~ ~ub~ect to Atta~k b~ moi~ture, and it wlll have a longer h~lf life. In ~ddlt~on, in contra~t to som~
prlor ~ct delivery vehicl~, a ~tyren~ d1vinylbenzen~
polym~ri~ bead of the p~e~ent inven~ion doe~ r~ot con-~a~n ~ny reat:tive~ group~ or polym~rlc s~ru¢tu~e whic~
may cauae a problem oP toxici~y, irritation or the like when applied ~opically to skls~.
Ano~-he~ advant~ge of a d~liv~ry vGahiale prepared in accordan~e wi~h ~he p~&~ent lnv~ntion i~ the ~ub-~tantial abs~nc~ o~ un~a~ted monomer d Thu~, ~ n a micoen~ap~ulation deli,very v~hi~lQ it may be dif~i~ult ~o ~emove unrea~ted monomer becau3e 1~ mi~ht beaom~
encapsul&ted along with the~ active ingredient in~ide o~
th~ membrane, Thl~ pr~blem iB ~pe~ially ~eute i~ ~ome prior a~t delivery veh,~les which l~tlllze ur~a-formal~
d~hyde microcap8ule~ wpl~h can create potential health problem~ .
Acoordinglyt it i~ ~ prinl~ry obje~t o~ the pre~en~
invention to provide a; dellve~y ~rehi~le ~or delivering an active ingredlent~ cont~olled time rele~q ov~r A
perlod of time to a skin sur~a~:a. Thi~ and ~urther obje~ts ant advant~e~l of the pre~ent intvention will becs~m~ apparen~c to ona o~ ordln~ry ~klll in the a~ in connaation with th3 d~ d de~crip~ion o~ ~h~ pre-ferr~d em~odlm~nt3 B13t forth below~
In a~ord~nce wit~ the presen~ in~en~ion, ~n 3 a~tiv~ lngr~dlen~ ~olul~ on 1~ 8u~pendsd in a ne . work o~
pore4 o~ a po~ous polyfneric bead whi~h i~ ~1 p~r~ed in a v~hi~le ~ubatan~all~ ible wi~h h~ ~olution~
~3~3~
. ~
A percutaneou~ ~bso~ption enharlcer will typ~cally he u~ed a3 a ~olvent ~or th~ active ingredi~nt.
A porou~ polymeric bead a~ordln~ ~o th~ pre~ent inventiorl can b~ pr~pa~ed 4y pol~merizing on~ or more rronomer~ ~y ~ fre~ radlaal suspenston polym~rizatiorl proces~. A monom~r or pair of comonomer~ i~ dis~olv~d in an in~rt porogen ~o form a ~olutlon whi~h i~ sus-psnded in a pha~e or 301V~lnt imcolopa~ible wlth the solu~lon .
An @xample of such a ph~ or ~olvent mlyht be water with 3tabil~zlng additive60 Af~r th~ 301ution ls unpended ln the pha3e, the olution . r~d phase are agit~ted ~o forrn a plurall~ of dropl~?ts o olu~ior~
suspended ln the pha~e. A~r th~3 forma ion of ~he lS plurality of droplet~, the monomer or monomer~ in the plurality of drDplets are activat~d to initiate polymerization rea~tion Ln whiah one ox morq monomer~
ar~3 polymeriz~d ~o fc~rm porous bead~ ha~ing a network of pore~ with ~he po~ogen held wlthin th~ network ~f pore~, The act~vatl~n may ba triggered by an lnltlator which is soluble in the morlomer ~olutlon, ~lternativ~ly, ac~ivation may be t~iggered by ~n energy ~ourc~ ~u~h a;
radia~cion. ~he inert poros~n w~ erve as an intern~l dlluen~ durln~ polymerl~atlon to in~roduce ~he de~lr~d ~5 spong~-llke macroporou 'cr~ ure or networX o;E pores into the ~ini ~h~d polym~ be~d ~ Tha in~rt porogen should not r~a~t w~h th~ monom~r pr~nt durlng polyme~izAtion or lnhibi~ th~ polymeriza~i~n. Th~
polym~ric ba~d may or m~y not 6w~ n th~ in~rt porogen/ Af~r th~ ~ormation o~ ~he pO~ polymerl~
~e~do, tl~e polymerl~ be~d~ are 3eparat~d ~rom th~ pha~e and subj~cted to on~ o~ n~ore pll~ifl~tior~ s~ep~, ~uch a~ w~h~ng, ~o ramo~re any unraa t~d monomer or lmpurlty ~rom the bead~, Porou~ ~olymerle beacl~ u~e~ul in the pre~nt in-vea~tlon Ga~ be Earepar~ed ut~ ing ~h~ gen~ral d~crip-tlon and pro ::edure~ ~t for~h ln Un~d Stateo P~tent ~3~
4,690,825, i~sued in Septe~ber 1987. ~owever, unles~ the active ingredient solution can serve as a porogen during the polymerization of the polymeric bead~, then the porogen mu~t be removed and replaced by said solution. Although these extra steps are not as desirable as using the solution as the porgen, satisfactory porous polymeric beads can still be obtained if the network of pores of said beads is substantially non-collapsible after removal of the porogen and remains substantially non-collapsible upon removal of the active ingredient.
The polymeric beads used in the present invention can be designed so as to control porosity and the particle diameter of the beads, which may be considered substantially spherical. Under identical poIymerization conditions, the porosity can be increased by increasing the ca~culated or t~heoretical cro~s-linking density or by increasing the porogen concentration in the solution. An increase in porosity will increase the surface area of the bead and hence the weight percent of the porgen which can be held within the bead. To decrease the particle diamete under identical poly-merization conditions, the agitation or the concentration of dispersion agents in the phase should be increased. By controlling the porosity and the particle diameter of the bead, a delivery vehicle suitable for use in the method of the present invention can be obtained. Generally speaking, it has been found that it is preferable for the bead to have a diameter from about 10 microns to about 100 microns, and have a calculated cross-linking in exces~ of about 10%. A
cross-linking of approximately 20% to 50% is preferred, with the range of approximately 25% to 30% being especially preferred. The pores in the beads of the present invention will typically range in diameter from approximately 10 angstrom~ to approximately 500 ang-13~P3~
stroms, ~he ~olution of th2 active inS~r~dient ~h~uld compri~ betwsen appro~clm~tely 5% to ~pproxlm~tely RO~
of the total w~ight o~ t~e compoQi~lon ~r d~livery Y~h~cl~ oompri~in~ the polymerl~ ~ead and said ~olu-~lonO
~o dls~tngul~h whether a porous polymeric ~ead posseq~es suffic~ient mechanl~al str~n~t~ to be u~ed a delivery vehi~le ~o:c providing con~rol}ed time-release o~ the ~olutloal aont~ining ~he ~tiv~ ingredi-1~ en~, the çompo~3ition aan be Qub~eated to a wettln~
~e~t. I~ the GompoRi~on }la~ a ~al~ ted. cro~-link-lng den31ty an~ a solukion con~e~ntration 3uch hat sub~
~tantially all of ~he ~ollltion ~il b~ r:ela~d from tbe network of pores when the bead i~ placed ln a ~ol-ven1:, ln whl~ thR ~olution i~ solubl~, ~or a su~fl-~
cient leng~h of tlm~ t~ we~ ~he b~ad, ~h~n ~he ~ompo~
tlon can ~ ed irl ths method o~ the pre~ant inven-tiorl .
A wetting test carl be perform~d by w~ighing a d.ry ~ample or materl~l ~o b~ ~e~ed contAin~ ng an origin~l amount o~ ~olutlon ~onka ~ ning the ~ctiv~ ingr~d~en~ .
The d~y sample i~ n Inix~d with a ~lv~nt in whlch the ~olution i~ soluble to ~orm ~ wet ~ample. Th~ w~t ~ample i~ ~h¢n Agl tat~d ~or a su~ici~3n~ lerlgth of tim~
to wet th~3 bead 1~ th~ dry ~mple 1~ eomp~is~d or~ ~
delivery vehlQle ~c~ording to thc pre~ant inv~rltion.
mount o~ ~olution relea~ed in~o ~ha ~olv~nt i8 then d~t~rmlne~, ~he amount o~ ~olu~lo~ rele~d i~
t~e ~olvent will b~ su1~stantially ~he ~ame a~ th~
original amoun~ of ~olution i~ the dry s~m~l~ consl~ked es~ent~ally of the d~liv~ry l~ehial~ wh~re~3 the re-lea~ad amount wlll be ~ub~tantially les~ ~h~n ~h~
o~lglnal ano~lnt ii~ the d~y ~mpl~ ~on~ained a ub~tan-tial amount o~ a g~l product o~ a n~icroe~ poul~ e~
p~oduc~. If ~h~ 301u~1On con~alnin~ ~he ~cti~ ~n~re~
dlen~ i8 not ~ch-3 poro~3n, then a w~lng t~t aan b~
uYed to ~onfirm tha~ ~he poro~en ~ no~ been en~ap~u-~L3~3~
1~
l~ad. Th~ conc~ntra'c~on of the A~ive ingredi~n~ ln ~uch a ~eli~ery v~hi~le ~an be d~ermln~d ~y ~ solvent w~tting ~ rollowed by an a~Ay, ~ h a~ ~ gr~vi-metrlc or W a~ay.
To utlllze a delL~ery vehicle in ~cord~nce wlth t}l~ me~hod o~ the presen~ lnv~n~ion, the delivery ~eh~cle ma~ be m~xsd ~ith a d~liv~ry medium t~ form a m1 xture which 1~ applled to a skin ~lr~ce . The ~olu-tlon of the ac~ivo in~redient i8 then releA~ rom the n~tworlc o~ pore~ by ~ $o~c:c or ~ergy. Thu~, ~y way o~
ex~mple only, ~h~ controlled time release migh~ oc~ur through dif~l~ion~ Be~auae th~ solution iB held Iprl-marily by ~bsorpt9 on) wlthin th~ net~o~c of pores o~
the pol~m~ric be~d~, ~h~a çon~entration of the ~olutl4n in tha medium will tend to be ~airly uniform and will not b~ a~ likely to agglom~rat~ or pool as 1~ the 901u ~ion had ~lmply been dlsperse~ within ~he medium. P~
the sol~tior~ i8 delivered to the skin $ur~ace, the per~
cu~aneou3 ab~orptlon enhan~ ol~ent ~ill protnote maxilnum t~e~modynamia a~tivity and penetrabili y ol~ th~
ac~ive lngred~ent, Ex~mplee oi~ pO3 ibla percutan~oua ~b~orptiorl enhancers inoludq p~op~lene ~lycol and p~o-pyl~ne c~otl~t~ which are use:Eul with corti~oateroid~l Numerous o~her pos31hl~ percut~neo~l~ ab~s~ption enh~nc-ere ar~ well-known ~o ona 8klll2tl ln the art ~nd migh~
in~luae, by ~ y or~ ~x~mpla only, dialky~ul~oxldQ~
~ving up to 22 carbons ln e~ch Al~cyl ~ro~lp, ~ ~ g a, dimethyl~ul~c~xlder dime~hylform~mida, ~im~athylac~ca mldo, dil~opxopyl a~ip~t~ opropyl myri~tat~ r~
~dro~urxn, tetrahydroi~ux~uryl ~ ohol, glycerol ?
~-me~hyl~2-pyrrolidon~ ~n~ ~ ~roduct avallabl~ under the tradem~rk ~ZONE ~l-dod~aylhex~hyd~o~2~aæ~pi~-2-one).
A number o~ dclivery ~edla may b~ u~d ln aon~una-~lon with ~h~ polymer bead d~livery ~e~tcle o~ th~
pres~nt lnventlon, and m~y b~ ~or~ulat~d u~ing materials and ~echnlq~e~ w~ known ~n ~h~ art, A
~ 33~
patrolatumtpolysilox~n~ba~ed d~livexy medium appropri-ate fo~ u~è ~,erein i~ d~cr1b~d in U.S~ P~tent No, 4,017,615. ~he d~llve~y ~edi~m ~hould b~ ~ubstantlally lmml~clble with th~ ~olutio~ contalning ~h~ active 5 ingredient, Pet~ola~um compound~ ranging in visco~ity from mineral oil to palr~f~ln waxe~ ar~ ~uit~bl~ m~dia, ~lt~ ~ p~raffin ~ompound h~ing approximately the conslstenc~ of petrolatum N~ ~petroleum jelly~ being e~peclally pre~rred as an oln~m~n~ ba~e. Poly~ilox~ne aompounds (also k~own A~ silico~e~ having appropriat~
vi~co~i~y charaaterlstic~ ~approxlma~ely ~O5 to 106 aen~ okes) a~e al30 sui~bl~ for U5~ as deliv6~ry media component~. Other ma~erial~ Xnown ~o the art, incl~di~g without excluslon adjuvan~s ~uch a~ beeswax, apermaaetl, paraffln waxes, and fatty acid~, alcohol~
~nd amldes having 10 to 22 carbon a~oms~, 3urfaatant~
thickeners, preservatlve~ hibi~ors and emul~i~ier3 may b~ ded within th~ deliv~ry m~dium usad har~in~
~he polym~r ~ead delivery vehi~le of th~ pre~e~
2~ inventlQn iB mech~nically ~trony because o~ the poly-meric structure of the bead and th~ ~egr~e o~ cro~-lln~in~ or copolymeri atio~. It i3 beli~v~d ~hat th~
bead oan be ~ncep~uallzed a~ ~ ~igld ~ponge, i.e., ~
otructural ne~work formed by thre~ dim~naional aroRa-linkln~ or ~opolym~riz~tion which lQave3 random ~pac~
or hole3 whlah ~ollect~lvely ~orm ~he net~ork ~ pore~.The polymer ~tructur~ or bead phy~i~ally hold~ the solutio~ and i~ then held or trapp~d untll an ex~ernal forc~ o~ energy r~le~s~ ha ~olu~ion ~rom th~ n~twork o~ por~s in th~ polym~rized bead~ ~owever, unlik~ ~
gel 1~ ~ich th~ polym~ric ~truc~u~al ne~work ~ollap~s ~h~n th~ ma~rial held wlthin s~ld network i8 r~mov~d or relea~e~, ~ dellvexy ~e~lcl~ or~ing to ~he pre~ent ~nvention mu~t po~e~ ~ c~rt~in minimum degr~e o~ calcul~ted ç~o~-linking den~y ~or a giv~n 801u-tion ~o a~ to qlve the en~ire ~tru~ure or be~d ~u~-: ~icient str~n~th to prev~nt ~ub~t~ntial ~hrlnkinq or 13~ 3~
collap9~ of th~ ~ead when ~h~ solution 18 re~oved ~romthe network ~f pore8 ~
Th~ pora aur~ace area, por~ dlam~ker and ~atlve lngredlent releaae char~cteri~tics o~ the b~ads o~ th~
5 pres~nt inv~ntlon may be ad~us~ed ~hrough proper ~electlon o~ a porogen. In gQnsral, pore sur~ac~ area, pore diameter and active lngredlen~ rele~ t~ may be in~ea5ed by u~ing a n~n-301ven~ type porogen auch as mineral oll or ~n Alip~atic hydro ~rbon ~uch ~
heptan~. Converaely, tho~e charaaterl ti~ may be reduced b~ u~ing ~ 901v~nt-type poro~n ~uch ~g toluen~.
The invention will b~ ~urth~r illu~trated in th.
example ~h~t foIlo~s wherein the d~livery v~hicl~ i9 copolymerized from styrene and divinylbenzene wh1ch ~s an espeolally p~efçrre~l ~omo~omer pair b~cau~ o~ ~h~
~be~i~al stabili~y of styrene divinylbenzsne. A~ would be appar~nt to on~ skilled in the ~rt, the term "dlvlnyl~enzene" aa ua~d in ~hi~ d~s~ription, a~ w~ll as i~ the ~ppended clalms, 1~ meant ~o ~n~lude pure dlvinylbenzen~ a~ well a~ ~omm6rcial diYi~ylbenzen~
which i~ r~ally a mixtura o~ divlnylb~nzene and ~thylvlnyl~en~ene, Other pre~rr~d comonom~r p~irs ~r~
~inyl steArat~ and divinylb~nzen@, and me~hyl me~h~cryl~te And ethylene glycol dlamethacrylate. In ~h~ foll~ing exampla th~ activ~ ingedient i~
~luoc~nonide, although oth~r ~-ero~d~ ~uah ~g fluocinolone acetonl~e, triam~inolonR a~tonid~, bet~meth~sone ~lar~-e, timo~e~onc a~e~te, hydrocortl~one, hydxoaorti~one acetat~, trl~mclnolone, prednl~olon~, predni~olo~e ~oeta~a, dex~m~th~one, boalomet~a~one dipropiona~, b3t~m~ha~0ne diproplcn~te, b~tam~thaæon~ ben~oate/ clocortolone pivalatej h~l~inonid~ ~lum~hason~ pl~al~t~ ~nd de~onido ~ay al80 b~ u~d. A num~er ~
an~l-ln~l~m~tory s~eroid~ sultabla ~or u~a in the pr~s~nt inven~ion hav~ bean dl~lo~e~ ~n U.8~ P~t~nt ~3~3 No~. 4,017,615, 3,365,446, 3,067,194, 3,364,203, 3,053,~33, and 3,513,162, ~or example.
~ 2000 ml ~our-necked reac~ion ~la~k equipped ~th a stlrrer, conde~ser, thermome~er, and nitrogen inlet w~ evacuatad and charged ~lt~ nitrogen ~00 ml deionized water, 6.4 ~rams of gum dr~bl~ and 6.4 gr~m~
o~ a ligno~ulfonate available from the American Can Co under th~ trademar~ Maxa~p~r~e N-2~, were cha~gea into the reaction flask. T~e mixtur~ was ~tirr~d ~or abou~
30 minute~. To thl3 mlx~ure was ~dded a fre~hly prapared s~lutlon of 85.6 gram~ of s~yrene ~99.8%
p~ity), 102.3 g~am~ cqmmer~l di~nylbe~zene ~55 divinylbanzene), 5,33 grams b~nzoyl peroxide (70 actlve ingredlent and 30~ ~ater), and 187.9 gram~ o~
toluene to ser~e a3 a poroge~, ~hq phA~e and olu~ion were a~itAted by a mechanical stlrrer who3~ ~tirr~ng rat~ of about 900-1200 rpm ~a8 A~ju~ted to obt~in a plurall~ of dropl~ having a ~roplat diam~ter sm~ller t~n abou~ 50 micron~. The gum arabic ~
ligno~ulfonate ~er~e to ~tabilize th~ plurality of dropl~t3. The reac~ion m~xture w~e hea~ed to about 78 degree~ Cel3ius whil~ ~ain~a~ ~ing a con3tant rate o~
stirring and pa~ lng ~ ~low ~tream o~ nitrogen through the reaatlon ve~8el. ~fte~ about ~ hour~ cro~-link~ng became no~iceable. ~he mlx~ur~ tlrred ano~r 22 ho~r~ ~t 78~ and wa~ then allowed to ao~L ~o room temperature, T~e por~U8 polymeri~ b~d~ wer~ removed from the xe~ion ~ia~ by ~ ratlon and wa~hed : several time3 wl~h ~at~r to remo~ g~m ~ab1c and lignosul~ona~e, ~ollo~ea by ~everal waahe~ og isoprop~nol/ace~one mlxed solvent (7s3 by volume) and were ~inally a~irr~d ~n 400 ml of i~opropanol~aceto~s mixed ~ol~nt ~7.3) or 20 hour~. Tho polymer wa~
filtered and dri~d overnlght at ~$C ln vauo. ~he yield wa~ prac~l~ally qu~n~itative~ The re~idu~l ~onomer~ such ~ ~tyren~, D~ and naphthal~na w~r~
~maller th~n ~bou~ 0~01~.
~l3C~3 The caloula~d or theo~etical cro~-linkin~
den~ity of th~ purlfied b~ads 18 30~ den~ity i~
aalculated by mul~iplying ~h~ weigh~ o~ diviny~benz~n~
~1û2.3 g~ by th~ purlty o~ the divinylbenzene (.55) to get the ~tual w~ight of pure divinyl~nzene whlch 18 then divided by t~e total weight of monom~r (102 . 3 g +
85. 6 g) .
~he surface area of a aampl~ of the purl~ied b~ad~
wa~ deter~lned by ~he ~.X,T. methoa ~o be 1.8 meters2~gr~m. The s.E,T. method 19 d~arlbed ln det~l in srunauer, 5, Emm~, P.E~" ~nd T~11Yr, E~, J,Am.~henl,so~ ~ 60, 309-16 (1930~ . The 3urfaae ar~ of the polymer ~n be rnodifi~a by uaing dif~r~nt porogen~
such as stable oil comp~und~ which might ln~lude, by lS way of example on~y, ~ neral oil, ve~3t~bl2 oil~ or ~ilicon oil~.
~11e p~rticle BiZ0 of th~ b~ad~ w~ determined by an optical ml~rosaope ~o be 60 mlcron~ or less wlth ~n a~tera~e approxlmat~ particle ~i2~3 d~am~ter of about 10 m~ orons .
The a~t~ ve ~ ngredlent fluoa~nonide (Syntex~ i~
~antrapped ln t~e b~3ads describ~d abov~ by ~po~ing the bead~ to a 1~ solu l~n of ~luoainon~de in propylen~
carbon~e t propylane gly~ol ~7 s 3) ~or a p~ri~d o~ tim~
~uf~ ci~3n~ to allow ~h~ beads ~ abaorh th~ a~tl~
ingr~di~n~c ~olutlon~ ~ho amount of ~ive ingrediant ~olutlon u~ed relati~ to th~ amoun~ o~ polyrn~r bead~
i8 adju3t~d ac~ordln~ to the de~ire~ ~inAl ~onoesltr~-t~ on of ac~ive ingredi~nt to b~ con~ained within th~
bea~ h~re a low ~lnal ~onaentra~lon ls d~lred, ~he ~c~ive ingredlen~ solt~ n may be ~urther dilut~d with ~ ~ol~ t ~u~:h a~ a~et~n~ thanc~l or ~h~nol prior to conlbinin~ th~ ~olutlon wl~h the be~d~ in or~der to achleva a ~U~Y~ien~ Amount of ~tar~ing ~olution to ~orm a ~lurr~r wi~h ~he be~. The diluent ~olvent i8 later r~moved by h~ating under ~ v~cuu~n.
~3r~3~
For example, to obtain b~ad~ wieh a ~lnal activ~
ingredient conc:entratlc:n of 0.OS~, 7~6 q o~ ~he polymer beads da~cribed above ls combln~ wi~h O . 4 g o~ a 1~
eolutlon ~f ~luocinon~ ~ in proE~ylen~ carbonat~ : pro-pylene glycol t7;3) ansl 14.~ g ~c~tone. The initial ~lurry i~ ~irred approxim~tel~ ev~y fi~ minute~ o~er a perlod o~ approximately ~hlrty mlnutes, aurln~ whi~
period th~ mlxtu~e be~ome~ cake-like and, 1nally, pow;
der-like ln con~l~ten~y. The re~ul~ing powder is then oven~dried for approxlmatQly three ho~re at 40 - 60 and ~ 5 ~ g ~ a~ w~ ~ ~h point th~ powd~x haa rea~h~d a cotlstan~ w~igh~ and the ac~one ha~ been remo~r~d9 Sim-llarly, a 0, 25~ fo~mul~tion may b~ achieved t~y mlxin~
~ . 8 5r polymer b~ad~, 3 . 2 g 3terold ~olutlon an~ 6 . 4 acetone as de3¢rlbed ~bo~e.
The ~ead~ contalning active lngr~dient a~ de~crih~
~d abo~ra may b~ u~illæed a~ prepared i~s a powd~r-rorm toplc~l ~or~ulAtion, or the ~eads may be com~in~d with other d~litrery medi.a ir~ ord~r to achi~Ya , e . g., ~n ointm~3nt, cr-3am, ~1 or other dosage form. In g~ner~l, ~he amount o~ polym~r bRads c:ont~ining ac~iva ingr~di-en~ tha~ ~u~ ~e combin~d wlth o'ch~3r d~llvery medla in ord~r to achi~ve ~ the~peu~i~ re~llt ~qill depe~ on th~ nature o~ th~ dell~rory m~dia and ~h~ partlcular active lngr~ierst. It has b~n found that th~ th~a~
p~utic an~i-ln~l~mmatory ~tivlty of fluocinonide-con-ing bead~ ln a petrolatum b~ed d~l~vexy m~dlurrl 1~
compardble, b~ed on ~.inal weigh~ conc~ntr~tion oi~ kha fluoc~nollide, ~o ~hat o~ 40mmer~1al~y-av~llable fluo~
cinonld~ olntmerlt~ ~uch aB ~ld~xo ~Syntaxl. Thus, olntment~ form~d usln~ th~ dell~rer~ ~rehiole~ o~ ~h~
pr~ent in~n~lon m~y employ a~tive ir~gradî~nt con~n-tration parallel to tho~ o~ typic!a1 olntment~
0.014 to 1~ by wsight. I ~ho~ld bq no~e~, bowever, ~h~ h~xapelltis~ally 0f~ct~ v~ ar~ in~la~atory contpo-~ition~ m . y inalud~ a~ llt~l~ a~ 0 ~ 00001~ by w~ight sterold a~ ingredierlt an~ a3 mu ::h a~ S~ by wQtgh~
~teroid or higher. A range o~ O . 01~ ~o o . 2~ iq paxtl-cularly u~e~ul, with O. 01~ to O. OS~ belng preEerred ~or th~ mor~ a~tlv~ ao~t~ co~ter~id~ ~uch a3 the fluoclnow n~des, and 0.01~ ~o 0,1~ belng prefer:re~ ~or le~
~c~ive cortico~eroi~ ~uch ~ th~ b~novate3 and the ~crlanlcinolones. When polym~r b~ad~ co~Aining A~tiV~:
ingredient a~e u~ed topically in powder ~orm, thera~-peuti~ anti-inf la~runatory actlvlty m~y be lower than that of ~ommer¢itll oin~ment, al~hough activlty 18 ln-~reased andlor provlded o~er longer ~im~ p~riod~ i~ tha polymer b~ad6~ are rubbed occa~onally to promo~e re~
le~ se o~ the a~lve ingredi~nt .
Suita~ oin~ments contalnln~ polymer b~ad~ with aa~lve lngredt en~ may be prep~red by conbining an ap-~5 propriA~e amount of the polymer 15e~d~ with p~t~ tum and an emul~i~ier 3uch a~ Amerchol CAB. To achl~ve a 0. 053 fluocinonide olnkmen~t ~or ~xample, 40 6 p~rt~ by wei~t (pbw) Amer~hol CAB, 32.2 pbw whlte petrolatum USP ~Ultl~na) and 50 . 7 pbw whita p~trolatum U~P were first com~ined and rllel~ed, ~rld 12~S pbtq 0.4~ ~luo¢i~lo-nide polymer b~de ~a~ than mix~d with the m~lted mix~
ture and cooled. Simil~rly, a 0.1~ ointmen~ wa~ oJ~
tained by comblnln~ 4.0 pbw Amerchol ~AB, 28.4 pbw ~rh~te petrolatum USP ~Ultlma~ and 4~.~ p~w whl~e p~tro~
~5 latum ~U~P) Wlth 25 . 0 pbw 0 . 4~ ~luocinonid0 ~ead~. A
O . 2~ oint:ment wa~ formula~ed by ~omblning Z . 6 pbw Amer-chol CA3, 1~,0 p~W ~hite petrol~kum ~UgPJ and 2~.4 pbw whlte petxol~.~um USP with S O ~ O pbw 0, 4 ~ ~luo~lnonld~
bead~. By ~ta~tlng with polymer b~ad~ cont~ining dif-~erent ~Amount~ Or a~tive in~redlent, ~he rela-i~e welgllt prs:portion o~ polymer bead deliv~ry v~hlc~ a~
be ~odulated, Th~ ef~a~y o~ th~ polymer beAd deliv~ry vehicle o~ the present in~n~io~a ha~ b@er~ demon~trated :Eor bo~h tbe Fowder and olntm~At ~orm~ o~ th~ be~dg~ ~Blng a vasocon~tri~tlon as~y~ T~i~ method i~ ba~ed orl th~
stoughton-~cKanz~ va~ocontriction a~aay ~o~ cor1;lc~-gL3~.~3~
~terold ~ormul~ti~n~ ~Mc~ zie, AL~ ~ and Stoughton, X. ~ ., "MQthod for Comparing P~r~ute.neo~ orption o~
sl;~roid~ , 8~, 6û~ 10 ~ 2)) . A11 .est preparation8 ~re placed in iden~ical oo~ta~ners, coded an~ asgigne~ by random ~ables ~o ~ ndi~ridu~l te~t 9itR8. The te~t 3ub~e~t~ ~r~a normal adult male and ~e~nale ~rolunteers not reaeiving any 3~e~0i~ ~nd ~ho hav~ no~ p~r~la~p~tea in any studie~ u~ing s~eroid~ for a~ lea~t our w@ek~ prior t~ teeting~ The for~arms o~
the ~ub~ec~s are prspared by gentle wa~hlng and dryLnSf.
Strips o~ double-Ad~aesi~re coat~3d Blenderm~ tap~ wi~h 7 x 7 mm p~epunch~d sgua~es (3M) ar@ appli~d kO ~a~h ~orearm to i~ola~e th~ application appropri-ate dos~ of th~3 ~est formulation lelth~r 2 mg or 3 mg) i~ then applie~ ~o t}le ~kin in ea~h ~u~r~ and î~
~pread alld rubbed wlth consl~tent pr~ure usin~ ~
clean H~ vlal at ~c~ ~pplic~tion site. In C21.8~g!3 wh~re powder-~orm polynler bead~ con~ ing ~luo~inonide 13 ~l~ed, the oraarm i~ lnvarted ~er ~ppll~a~lorl ~nd each indivldual site i~ gently bru~hed with a cl~an ~quare o~ gauze to rem~re exc¢~s polymex ~ead~ ~ pro~
~ectlv~ aage i~ ~pplied over tha ~ on the for~arm de~lgnat~3d ~or "open" applioa~ion, On th~ oth~r ~xm ~noccluded~) t~ ~ite~ are cov~r~d wi~h Saran Wrap~
'c~e m~rgin~ ~al~d wl h t~p~ ~nd a p~o~e~v~ ~ge place~ ovar th~ e~. Atc~ 8iX hour~3 o:E ~xpo~ure o~
the ~kln t~ the corti~oat~rold prep2lra~lon~, all th~
tapes ar~ r~mov~d and the ~or~arm~ are~ wa~hed.
S~oring in th~ a~ay ~ prefoxmed by t~o experl 3~ ~nced ob~r~ers ~ho in~l~p~ndon~ly ~aore the pr~aen~e or ai)~enc~e o~ ~ra~scon~trlation ana th~ d~ e ~nd bl~nch~
ing ~t a, ~4 and 3~ hour~ after t~e time o~ applic~ior o f th6 ~o~:mulations to ~he ~lte~ .
A~ ~videncod ln ~a}:le 1, tl~e powder ~orm polymQr bead formul~,~ion~ o~ th~ prea~3~t in re~ntiorl a~hlev~
~igni~i~an~ vA3o~onstrict~on M~i ~ompaxe~ to comm~r~ial-ly-~up~lied Lidex~ ~luocinonld~ oln~m~n~ ~ya~ no~
, using a polymer be~d ~llvery v~hi~le~ Although va~o-constriction due ~o ~h~ po~der ~orm polym0r bead3 18 ~ome~at le~ kha~ tha~ ob~erv~d wl~b the Lid~X~ oi~t-ment, thi~ dl~fe~enc~ may be du~ to the fact thAt ex-ce~ powder formul~tion i~ bru~h~d o~ after applica-tlo~ to th~ for~arms. ~bl~ ~ demon~ate~ that inte~
mittent ru~bing o the powder-form formulatlon~ acts to pxo~ote and prolong va~oconstrlctlon a~ivity. Table 3 demonstra~e~ tha~ th~ polym~r bead d~liv~ry v~hiale of the pr~ent inventlon, w~en applied in an ointment form ~omparable to that of commercially~upplle~ fluocino~
nide ointmer~t, ac:hlev~ a l~vel oX v~socon~triction ap-proximately e~uAl to that of ~he comm~r~lly~3upplled product~ ~his effec~ i~ ac~ie~ed indepa~d~n~ o~ any rubbin~ o~ t~e polym~ baad olntmsn~ sub~equ~nt to ap-plicatlon, It may ~e expected t~at ~uch rubbing willfur~her en~ance v~soconstric~ion activity attribu~able ~o ~he deli~ry ~ehlcl~ of th~ pre~en~ lnv~ntlonO
._ ~........................................... .
-- , , ~3~3~
.. ~o ~L~ 1 ~
9~A~Lh~
24 32 ~ot~1 4 10P'~UOCIN~NIDE~ FORM~II.ATION
Site~ R~3~ponding ~ 30.0 62.5 S0.0 162.5 Int~nslt:y o~
15P~e~ponee ~ 22.9 2~9 1~.7 ~,5 ~D~:
~lt~8 Re~ponding (4): 62.5 5~.3 ~S.~ 143,8 20Int~nslty o~
Re~ponse (%): 25~0 18.~ 8~3 S~.1 Oint~ment 10 05 Q lud~d A~p1i~ation~
;~5~it~3 R~spondin~ 100,0 a7.5 75.0 262.5 In~n~ity o~
Reopsn~ ~%) ~ 7~9 ~3~3 27.1 133,3 Oio-=n~
O ~ ioll ~
Si~ R2~ponding (%~a ~ ao.o 93~8 2~7~6 Int~slty 0~
Pcespona~ . t; 31. 3 1~9, 7 35 N~ Do~ag~ wa~ g o~ poly~ner powder, ~th ent~ppe~
:E1UQC:1nOn1dl~ [0,4~), or 2 3n~ T-idexO 0.05~ :eluocinonid~
ointm~n~. Te~ 3it~ r~ ru~b~d a~ tim~ z~ro, wa~h~d a~
tim~ ~ hour~, and r~d a~ the t~me~ dt ¢~a.
.
.
lL3~3~
-~ 21 T~L~ 2 ~C~c on trll~tlon Ef f~ o~ Polymer Po&~d~y~ For~Qula~lon~
~
}lours At~r Appllcatlon 8 24 3~ Total FL~INO2~IDE FORMU~A~ION
Sit 2a) P~espondln~
~Inore~e ~) 25~0 1~.5 3103 6Zo8 Int0nsi~y of Re~p~n~e rea~e ~) 8.3 4~1 10.4 2208 1~
Bit~s ~esp~ndirlg (~n~r~ase %) 0 31.3 31-3 62.6 Int-e~el~y o~ ~e~ons~
(Increas~ 10.4 12~5 22.9 Sltea Responding ( InoreA~e ~ . 7 1~ ~ 52 5 . 0 1~, 8 Int~nsi~y c~ e~pons~
2S~nc~e~e ~) -10.4 4.1 10.4 4,,1 ,' NC~Eo ~o~ag~ wa~ 2 mg o~ polym~r powd~r, with ~ntr~pp~d ~luo~inonide at indiqat~d pxopo~tlon. Ul ~e~t ~te~
werQ l~f~ open ~unoccllld~d~ and w~e rubbed an~ brush~d o~ at tim~ zero. ~on~roI powde~ ee we~e ~ehed at time 6 hc~ur~7 ~-rub~ed powds~ ~it~3~ w~ ubb~ ~t 6, 8, ~nd 24 hours~ R~adlng~ ~r~ ma~e a~ ~itne~ dic~e~
D~ta r~pr~3en~ pet~cerlt r~ading~ tzlk~n at r~ rubb~ ~lit@~l minu~ p~r~nt ~eadin~s tak~n ~t ~orr~pon~lng control glt~, :' .... .
~3~3 T_ Va3scon~trl~t~0n_ A-~e ~i ~
~A~
8 _24 32T~t~l FLUO~IN~NIDR Fo~uLATroN
Site~ Re~pontin~ ~%) ~7, ~ 81. 3 237 . 6 Inten~ity of Re3posa~ 75.0 29.229~2 133.4 Sit~ Re~pondla~ ~%) 87.5 6~.5~R.8 ~18.8 In~en8ity of ~bspon~e (X~ 72,9 20,R25.0 11~.7 Sitos Re~pondlng tX) 87.5 62.5~8.3 Z1~.a Int~nal~y of Reaponse t~) 66.7 25.022.9 114.6 Sitoo Re~pondin8 ~%) 93.8 75.081,3 250.1 Int~n~ity of Raoponse ~ 72.9 27.12~-2 129,2 ~ol e ~, Si~ea R~spondin~ (~) 75 . 0 81. 3~1. 3 237 . 6 In~n~ity o~ Ro~pon~ ~X) 58.3 ~9.2~9.Z 116.7 8i o~ Re~ponding ~2) ~3. ~ 62. S37 . S 193. ~
Int~nstty o~ Reopon~ (X) ~8,8 2S,012.5 l06.3 ~ite~ R2dpoading (~) ~3.8 68.868.8 231.4 Ine~n~ity o~ R~spon~0 (~) 7~,2 27.12~ 9.2 8lgeÆ Re~pondln~ ~X3 87 . 5 7~ . 0 87 . 5 250 . 0 Int~ll31ty o~ Rsspon~ 77,1 27.133.3 137.5 NGTE: ~o~ag~ ~o 3 ~ o~ ~o~olstu~baoe~ oln~ nt contsirl~n~ poly-~r po~d~ th ent~pped ~luocirlonlt~ ~t ind~cAeed proportiolt, or 3 21l~ Lide~ 0.0S~ ~luoclno~ld~ ol~t~an~. T~ lt~ w~ ~bb~d at tiD~ z~o, wa~he~ ~t tl~ 6 hours, ~t r~d ~t th~ tl~e~ dlcatetO
, ..
~3~
In an additional study, ~luoclnonlde wa~ di~olved in a ~0/70 p~opylene glycol/propylene carbQ~ats ~y9t~m and entrapp~d in the microspong~3 sponge entr~pm~n~ e ~em in a~cordance with th~ pre~en~ inven~iorl . The 5 degree of vasooons~rl~tion prod~e~ served ~ an indi-e~tor o~ ~h~ r~lea~e o~ the ~ort~costerold solukion from the micro~ponge entrap~ent ~y~tsm. Equal amount~
of tha micro~copio spong~ partlal~s wer~ ~lre~tly ap~
plled to ~man ~o~arm~, rubb~d gently, and ~ha exc~
powder brushed of~. On one Arm, no ~urther ~pplication or ~nlp~la~ion w~ made. On ~he o~her arm, ~he 31te of initial appllc~tlon wa~ qen~ly ~ubbe~ at 7, Z3, and 31 hours, but no additional product was added.
~a~ocon3trlc~10n re~pon~e~ were mea~ured and r~-cord~ ~t 8 t 24, and 32 hour~ and the re~ult~ are pre-sentad in Table 4~ ~h~ ln~r2~8e2 ~nd ontin~ed v~
con~tr~ction produ~ad in th~ arm that wa~ rubbed ~e~er-al time~ is deflnitive evlden~e of ~he demand and ~
~ained relea~e o~ the cortico~roid ~olutlon rom the micro~ponge entrapment sy~em.
~, . . . . . .
~3~3~
,.
20 ~ 3 ~ 2~ 33~
~ ~ '~ ~ ~ ~ o ~ ~ ~ ~ ~ ~ ~ ~ ~
z s ~ ; I ¦ ~ 3 c ; ~ 3 D ~ D ~ 3 ~ e . .
.
3~3~3~
.~ 25 H~llng ~ully de~crib~d khe pr~s~nt lnv~n~lon, it will be apparent ~rom the above d~cription that vari-ous modlf~tiOns irl the speci~ia compositior.~, proce-dure3, method~ ~nd proce~es ~ay bf3 made wi~hin th~
~cope o~ ~he inv~ant~ on. ~here~ore, the lnvention 1~
not in~ended to b~ liml~ed to the p~rticular cc: mpo i-tions, pro~e~3~s or m~thods excep~ a~ m~y ~e required hy t~e l~w~ul 8C:0p~ 0~ th~ following clalm~
,, ,
bead oan be ~ncep~uallzed a~ ~ ~igld ~ponge, i.e., ~
otructural ne~work formed by thre~ dim~naional aroRa-linkln~ or ~opolym~riz~tion which lQave3 random ~pac~
or hole3 whlah ~ollect~lvely ~orm ~he net~ork ~ pore~.The polymer ~tructur~ or bead phy~i~ally hold~ the solutio~ and i~ then held or trapp~d untll an ex~ernal forc~ o~ energy r~le~s~ ha ~olu~ion ~rom th~ n~twork o~ por~s in th~ polym~rized bead~ ~owever, unlik~ ~
gel 1~ ~ich th~ polym~ric ~truc~u~al ne~work ~ollap~s ~h~n th~ ma~rial held wlthin s~ld network i8 r~mov~d or relea~e~, ~ dellvexy ~e~lcl~ or~ing to ~he pre~ent ~nvention mu~t po~e~ ~ c~rt~in minimum degr~e o~ calcul~ted ç~o~-linking den~y ~or a giv~n 801u-tion ~o a~ to qlve the en~ire ~tru~ure or be~d ~u~-: ~icient str~n~th to prev~nt ~ub~t~ntial ~hrlnkinq or 13~ 3~
collap9~ of th~ ~ead when ~h~ solution 18 re~oved ~romthe network ~f pore8 ~
Th~ pora aur~ace area, por~ dlam~ker and ~atlve lngredlent releaae char~cteri~tics o~ the b~ads o~ th~
5 pres~nt inv~ntlon may be ad~us~ed ~hrough proper ~electlon o~ a porogen. In gQnsral, pore sur~ac~ area, pore diameter and active lngredlen~ rele~ t~ may be in~ea5ed by u~ing a n~n-301ven~ type porogen auch as mineral oll or ~n Alip~atic hydro ~rbon ~uch ~
heptan~. Converaely, tho~e charaaterl ti~ may be reduced b~ u~ing ~ 901v~nt-type poro~n ~uch ~g toluen~.
The invention will b~ ~urth~r illu~trated in th.
example ~h~t foIlo~s wherein the d~livery v~hicl~ i9 copolymerized from styrene and divinylbenzene wh1ch ~s an espeolally p~efçrre~l ~omo~omer pair b~cau~ o~ ~h~
~be~i~al stabili~y of styrene divinylbenzsne. A~ would be appar~nt to on~ skilled in the ~rt, the term "dlvlnyl~enzene" aa ua~d in ~hi~ d~s~ription, a~ w~ll as i~ the ~ppended clalms, 1~ meant ~o ~n~lude pure dlvinylbenzen~ a~ well a~ ~omm6rcial diYi~ylbenzen~
which i~ r~ally a mixtura o~ divlnylb~nzene and ~thylvlnyl~en~ene, Other pre~rr~d comonom~r p~irs ~r~
~inyl steArat~ and divinylb~nzen@, and me~hyl me~h~cryl~te And ethylene glycol dlamethacrylate. In ~h~ foll~ing exampla th~ activ~ ingedient i~
~luoc~nonide, although oth~r ~-ero~d~ ~uah ~g fluocinolone acetonl~e, triam~inolonR a~tonid~, bet~meth~sone ~lar~-e, timo~e~onc a~e~te, hydrocortl~one, hydxoaorti~one acetat~, trl~mclnolone, prednl~olon~, predni~olo~e ~oeta~a, dex~m~th~one, boalomet~a~one dipropiona~, b3t~m~ha~0ne diproplcn~te, b~tam~thaæon~ ben~oate/ clocortolone pivalatej h~l~inonid~ ~lum~hason~ pl~al~t~ ~nd de~onido ~ay al80 b~ u~d. A num~er ~
an~l-ln~l~m~tory s~eroid~ sultabla ~or u~a in the pr~s~nt inven~ion hav~ bean dl~lo~e~ ~n U.8~ P~t~nt ~3~3 No~. 4,017,615, 3,365,446, 3,067,194, 3,364,203, 3,053,~33, and 3,513,162, ~or example.
~ 2000 ml ~our-necked reac~ion ~la~k equipped ~th a stlrrer, conde~ser, thermome~er, and nitrogen inlet w~ evacuatad and charged ~lt~ nitrogen ~00 ml deionized water, 6.4 ~rams of gum dr~bl~ and 6.4 gr~m~
o~ a ligno~ulfonate available from the American Can Co under th~ trademar~ Maxa~p~r~e N-2~, were cha~gea into the reaction flask. T~e mixtur~ was ~tirr~d ~or abou~
30 minute~. To thl3 mlx~ure was ~dded a fre~hly prapared s~lutlon of 85.6 gram~ of s~yrene ~99.8%
p~ity), 102.3 g~am~ cqmmer~l di~nylbe~zene ~55 divinylbanzene), 5,33 grams b~nzoyl peroxide (70 actlve ingredlent and 30~ ~ater), and 187.9 gram~ o~
toluene to ser~e a3 a poroge~, ~hq phA~e and olu~ion were a~itAted by a mechanical stlrrer who3~ ~tirr~ng rat~ of about 900-1200 rpm ~a8 A~ju~ted to obt~in a plurall~ of dropl~ having a ~roplat diam~ter sm~ller t~n abou~ 50 micron~. The gum arabic ~
ligno~ulfonate ~er~e to ~tabilize th~ plurality of dropl~t3. The reac~ion m~xture w~e hea~ed to about 78 degree~ Cel3ius whil~ ~ain~a~ ~ing a con3tant rate o~
stirring and pa~ lng ~ ~low ~tream o~ nitrogen through the reaatlon ve~8el. ~fte~ about ~ hour~ cro~-link~ng became no~iceable. ~he mlx~ur~ tlrred ano~r 22 ho~r~ ~t 78~ and wa~ then allowed to ao~L ~o room temperature, T~e por~U8 polymeri~ b~d~ wer~ removed from the xe~ion ~ia~ by ~ ratlon and wa~hed : several time3 wl~h ~at~r to remo~ g~m ~ab1c and lignosul~ona~e, ~ollo~ea by ~everal waahe~ og isoprop~nol/ace~one mlxed solvent (7s3 by volume) and were ~inally a~irr~d ~n 400 ml of i~opropanol~aceto~s mixed ~ol~nt ~7.3) or 20 hour~. Tho polymer wa~
filtered and dri~d overnlght at ~$C ln vauo. ~he yield wa~ prac~l~ally qu~n~itative~ The re~idu~l ~onomer~ such ~ ~tyren~, D~ and naphthal~na w~r~
~maller th~n ~bou~ 0~01~.
~l3C~3 The caloula~d or theo~etical cro~-linkin~
den~ity of th~ purlfied b~ads 18 30~ den~ity i~
aalculated by mul~iplying ~h~ weigh~ o~ diviny~benz~n~
~1û2.3 g~ by th~ purlty o~ the divinylbenzene (.55) to get the ~tual w~ight of pure divinyl~nzene whlch 18 then divided by t~e total weight of monom~r (102 . 3 g +
85. 6 g) .
~he surface area of a aampl~ of the purl~ied b~ad~
wa~ deter~lned by ~he ~.X,T. methoa ~o be 1.8 meters2~gr~m. The s.E,T. method 19 d~arlbed ln det~l in srunauer, 5, Emm~, P.E~" ~nd T~11Yr, E~, J,Am.~henl,so~ ~ 60, 309-16 (1930~ . The 3urfaae ar~ of the polymer ~n be rnodifi~a by uaing dif~r~nt porogen~
such as stable oil comp~und~ which might ln~lude, by lS way of example on~y, ~ neral oil, ve~3t~bl2 oil~ or ~ilicon oil~.
~11e p~rticle BiZ0 of th~ b~ad~ w~ determined by an optical ml~rosaope ~o be 60 mlcron~ or less wlth ~n a~tera~e approxlmat~ particle ~i2~3 d~am~ter of about 10 m~ orons .
The a~t~ ve ~ ngredlent fluoa~nonide (Syntex~ i~
~antrapped ln t~e b~3ads describ~d abov~ by ~po~ing the bead~ to a 1~ solu l~n of ~luoainon~de in propylen~
carbon~e t propylane gly~ol ~7 s 3) ~or a p~ri~d o~ tim~
~uf~ ci~3n~ to allow ~h~ beads ~ abaorh th~ a~tl~
ingr~di~n~c ~olutlon~ ~ho amount of ~ive ingrediant ~olutlon u~ed relati~ to th~ amoun~ o~ polyrn~r bead~
i8 adju3t~d ac~ordln~ to the de~ire~ ~inAl ~onoesltr~-t~ on of ac~ive ingredi~nt to b~ con~ained within th~
bea~ h~re a low ~lnal ~onaentra~lon ls d~lred, ~he ~c~ive ingredlen~ solt~ n may be ~urther dilut~d with ~ ~ol~ t ~u~:h a~ a~et~n~ thanc~l or ~h~nol prior to conlbinin~ th~ ~olutlon wl~h the be~d~ in or~der to achleva a ~U~Y~ien~ Amount of ~tar~ing ~olution to ~orm a ~lurr~r wi~h ~he be~. The diluent ~olvent i8 later r~moved by h~ating under ~ v~cuu~n.
~3r~3~
For example, to obtain b~ad~ wieh a ~lnal activ~
ingredient conc:entratlc:n of 0.OS~, 7~6 q o~ ~he polymer beads da~cribed above ls combln~ wi~h O . 4 g o~ a 1~
eolutlon ~f ~luocinon~ ~ in proE~ylen~ carbonat~ : pro-pylene glycol t7;3) ansl 14.~ g ~c~tone. The initial ~lurry i~ ~irred approxim~tel~ ev~y fi~ minute~ o~er a perlod o~ approximately ~hlrty mlnutes, aurln~ whi~
period th~ mlxtu~e be~ome~ cake-like and, 1nally, pow;
der-like ln con~l~ten~y. The re~ul~ing powder is then oven~dried for approxlmatQly three ho~re at 40 - 60 and ~ 5 ~ g ~ a~ w~ ~ ~h point th~ powd~x haa rea~h~d a cotlstan~ w~igh~ and the ac~one ha~ been remo~r~d9 Sim-llarly, a 0, 25~ fo~mul~tion may b~ achieved t~y mlxin~
~ . 8 5r polymer b~ad~, 3 . 2 g 3terold ~olutlon an~ 6 . 4 acetone as de3¢rlbed ~bo~e.
The ~ead~ contalning active lngr~dient a~ de~crih~
~d abo~ra may b~ u~illæed a~ prepared i~s a powd~r-rorm toplc~l ~or~ulAtion, or the ~eads may be com~in~d with other d~litrery medi.a ir~ ord~r to achi~Ya , e . g., ~n ointm~3nt, cr-3am, ~1 or other dosage form. In g~ner~l, ~he amount o~ polym~r bRads c:ont~ining ac~iva ingr~di-en~ tha~ ~u~ ~e combin~d wlth o'ch~3r d~llvery medla in ord~r to achi~ve ~ the~peu~i~ re~llt ~qill depe~ on th~ nature o~ th~ dell~rory m~dia and ~h~ partlcular active lngr~ierst. It has b~n found that th~ th~a~
p~utic an~i-ln~l~mmatory ~tivlty of fluocinonide-con-ing bead~ ln a petrolatum b~ed d~l~vexy m~dlurrl 1~
compardble, b~ed on ~.inal weigh~ conc~ntr~tion oi~ kha fluoc~nollide, ~o ~hat o~ 40mmer~1al~y-av~llable fluo~
cinonld~ olntmerlt~ ~uch aB ~ld~xo ~Syntaxl. Thus, olntment~ form~d usln~ th~ dell~rer~ ~rehiole~ o~ ~h~
pr~ent in~n~lon m~y employ a~tive ir~gradî~nt con~n-tration parallel to tho~ o~ typic!a1 olntment~
0.014 to 1~ by wsight. I ~ho~ld bq no~e~, bowever, ~h~ h~xapelltis~ally 0f~ct~ v~ ar~ in~la~atory contpo-~ition~ m . y inalud~ a~ llt~l~ a~ 0 ~ 00001~ by w~ight sterold a~ ingredierlt an~ a3 mu ::h a~ S~ by wQtgh~
~teroid or higher. A range o~ O . 01~ ~o o . 2~ iq paxtl-cularly u~e~ul, with O. 01~ to O. OS~ belng preEerred ~or th~ mor~ a~tlv~ ao~t~ co~ter~id~ ~uch a3 the fluoclnow n~des, and 0.01~ ~o 0,1~ belng prefer:re~ ~or le~
~c~ive cortico~eroi~ ~uch ~ th~ b~novate3 and the ~crlanlcinolones. When polym~r b~ad~ co~Aining A~tiV~:
ingredient a~e u~ed topically in powder ~orm, thera~-peuti~ anti-inf la~runatory actlvlty m~y be lower than that of ~ommer¢itll oin~ment, al~hough activlty 18 ln-~reased andlor provlded o~er longer ~im~ p~riod~ i~ tha polymer b~ad6~ are rubbed occa~onally to promo~e re~
le~ se o~ the a~lve ingredi~nt .
Suita~ oin~ments contalnln~ polymer b~ad~ with aa~lve lngredt en~ may be prep~red by conbining an ap-~5 propriA~e amount of the polymer 15e~d~ with p~t~ tum and an emul~i~ier 3uch a~ Amerchol CAB. To achl~ve a 0. 053 fluocinonide olnkmen~t ~or ~xample, 40 6 p~rt~ by wei~t (pbw) Amer~hol CAB, 32.2 pbw whlte petrolatum USP ~Ultl~na) and 50 . 7 pbw whita p~trolatum U~P were first com~ined and rllel~ed, ~rld 12~S pbtq 0.4~ ~luo¢i~lo-nide polymer b~de ~a~ than mix~d with the m~lted mix~
ture and cooled. Simil~rly, a 0.1~ ointmen~ wa~ oJ~
tained by comblnln~ 4.0 pbw Amerchol ~AB, 28.4 pbw ~rh~te petrolatum USP ~Ultlma~ and 4~.~ p~w whl~e p~tro~
~5 latum ~U~P) Wlth 25 . 0 pbw 0 . 4~ ~luocinonid0 ~ead~. A
O . 2~ oint:ment wa~ formula~ed by ~omblning Z . 6 pbw Amer-chol CA3, 1~,0 p~W ~hite petrol~kum ~UgPJ and 2~.4 pbw whlte petxol~.~um USP with S O ~ O pbw 0, 4 ~ ~luo~lnonld~
bead~. By ~ta~tlng with polymer b~ad~ cont~ining dif-~erent ~Amount~ Or a~tive in~redlent, ~he rela-i~e welgllt prs:portion o~ polymer bead deliv~ry v~hlc~ a~
be ~odulated, Th~ ef~a~y o~ th~ polymer beAd deliv~ry vehicle o~ the present in~n~io~a ha~ b@er~ demon~trated :Eor bo~h tbe Fowder and olntm~At ~orm~ o~ th~ be~dg~ ~Blng a vasocon~tri~tlon as~y~ T~i~ method i~ ba~ed orl th~
stoughton-~cKanz~ va~ocontriction a~aay ~o~ cor1;lc~-gL3~.~3~
~terold ~ormul~ti~n~ ~Mc~ zie, AL~ ~ and Stoughton, X. ~ ., "MQthod for Comparing P~r~ute.neo~ orption o~
sl;~roid~ , 8~, 6û~ 10 ~ 2)) . A11 .est preparation8 ~re placed in iden~ical oo~ta~ners, coded an~ asgigne~ by random ~ables ~o ~ ndi~ridu~l te~t 9itR8. The te~t 3ub~e~t~ ~r~a normal adult male and ~e~nale ~rolunteers not reaeiving any 3~e~0i~ ~nd ~ho hav~ no~ p~r~la~p~tea in any studie~ u~ing s~eroid~ for a~ lea~t our w@ek~ prior t~ teeting~ The for~arms o~
the ~ub~ec~s are prspared by gentle wa~hlng and dryLnSf.
Strips o~ double-Ad~aesi~re coat~3d Blenderm~ tap~ wi~h 7 x 7 mm p~epunch~d sgua~es (3M) ar@ appli~d kO ~a~h ~orearm to i~ola~e th~ application appropri-ate dos~ of th~3 ~est formulation lelth~r 2 mg or 3 mg) i~ then applie~ ~o t}le ~kin in ea~h ~u~r~ and î~
~pread alld rubbed wlth consl~tent pr~ure usin~ ~
clean H~ vlal at ~c~ ~pplic~tion site. In C21.8~g!3 wh~re powder-~orm polynler bead~ con~ ing ~luo~inonide 13 ~l~ed, the oraarm i~ lnvarted ~er ~ppll~a~lorl ~nd each indivldual site i~ gently bru~hed with a cl~an ~quare o~ gauze to rem~re exc¢~s polymex ~ead~ ~ pro~
~ectlv~ aage i~ ~pplied over tha ~ on the for~arm de~lgnat~3d ~or "open" applioa~ion, On th~ oth~r ~xm ~noccluded~) t~ ~ite~ are cov~r~d wi~h Saran Wrap~
'c~e m~rgin~ ~al~d wl h t~p~ ~nd a p~o~e~v~ ~ge place~ ovar th~ e~. Atc~ 8iX hour~3 o:E ~xpo~ure o~
the ~kln t~ the corti~oat~rold prep2lra~lon~, all th~
tapes ar~ r~mov~d and the ~or~arm~ are~ wa~hed.
S~oring in th~ a~ay ~ prefoxmed by t~o experl 3~ ~nced ob~r~ers ~ho in~l~p~ndon~ly ~aore the pr~aen~e or ai)~enc~e o~ ~ra~scon~trlation ana th~ d~ e ~nd bl~nch~
ing ~t a, ~4 and 3~ hour~ after t~e time o~ applic~ior o f th6 ~o~:mulations to ~he ~lte~ .
A~ ~videncod ln ~a}:le 1, tl~e powder ~orm polymQr bead formul~,~ion~ o~ th~ prea~3~t in re~ntiorl a~hlev~
~igni~i~an~ vA3o~onstrict~on M~i ~ompaxe~ to comm~r~ial-ly-~up~lied Lidex~ ~luocinonld~ oln~m~n~ ~ya~ no~
, using a polymer be~d ~llvery v~hi~le~ Although va~o-constriction due ~o ~h~ po~der ~orm polym0r bead3 18 ~ome~at le~ kha~ tha~ ob~erv~d wl~b the Lid~X~ oi~t-ment, thi~ dl~fe~enc~ may be du~ to the fact thAt ex-ce~ powder formul~tion i~ bru~h~d o~ after applica-tlo~ to th~ for~arms. ~bl~ ~ demon~ate~ that inte~
mittent ru~bing o the powder-form formulatlon~ acts to pxo~ote and prolong va~oconstrlctlon a~ivity. Table 3 demonstra~e~ tha~ th~ polym~r bead d~liv~ry v~hiale of the pr~ent inventlon, w~en applied in an ointment form ~omparable to that of commercially~upplle~ fluocino~
nide ointmer~t, ac:hlev~ a l~vel oX v~socon~triction ap-proximately e~uAl to that of ~he comm~r~lly~3upplled product~ ~his effec~ i~ ac~ie~ed indepa~d~n~ o~ any rubbin~ o~ t~e polym~ baad olntmsn~ sub~equ~nt to ap-plicatlon, It may ~e expected t~at ~uch rubbing willfur~her en~ance v~soconstric~ion activity attribu~able ~o ~he deli~ry ~ehlcl~ of th~ pre~en~ lnv~ntlonO
._ ~........................................... .
-- , , ~3~3~
.. ~o ~L~ 1 ~
9~A~Lh~
24 32 ~ot~1 4 10P'~UOCIN~NIDE~ FORM~II.ATION
Site~ R~3~ponding ~ 30.0 62.5 S0.0 162.5 Int~nslt:y o~
15P~e~ponee ~ 22.9 2~9 1~.7 ~,5 ~D~:
~lt~8 Re~ponding (4): 62.5 5~.3 ~S.~ 143,8 20Int~nslty o~
Re~ponse (%): 25~0 18.~ 8~3 S~.1 Oint~ment 10 05 Q lud~d A~p1i~ation~
;~5~it~3 R~spondin~ 100,0 a7.5 75.0 262.5 In~n~ity o~
Reopsn~ ~%) ~ 7~9 ~3~3 27.1 133,3 Oio-=n~
O ~ ioll ~
Si~ R2~ponding (%~a ~ ao.o 93~8 2~7~6 Int~slty 0~
Pcespona~ . t; 31. 3 1~9, 7 35 N~ Do~ag~ wa~ g o~ poly~ner powder, ~th ent~ppe~
:E1UQC:1nOn1dl~ [0,4~), or 2 3n~ T-idexO 0.05~ :eluocinonid~
ointm~n~. Te~ 3it~ r~ ru~b~d a~ tim~ z~ro, wa~h~d a~
tim~ ~ hour~, and r~d a~ the t~me~ dt ¢~a.
.
.
lL3~3~
-~ 21 T~L~ 2 ~C~c on trll~tlon Ef f~ o~ Polymer Po&~d~y~ For~Qula~lon~
~
}lours At~r Appllcatlon 8 24 3~ Total FL~INO2~IDE FORMU~A~ION
Sit 2a) P~espondln~
~Inore~e ~) 25~0 1~.5 3103 6Zo8 Int0nsi~y of Re~p~n~e rea~e ~) 8.3 4~1 10.4 2208 1~
Bit~s ~esp~ndirlg (~n~r~ase %) 0 31.3 31-3 62.6 Int-e~el~y o~ ~e~ons~
(Increas~ 10.4 12~5 22.9 Sltea Responding ( InoreA~e ~ . 7 1~ ~ 52 5 . 0 1~, 8 Int~nsi~y c~ e~pons~
2S~nc~e~e ~) -10.4 4.1 10.4 4,,1 ,' NC~Eo ~o~ag~ wa~ 2 mg o~ polym~r powd~r, with ~ntr~pp~d ~luo~inonide at indiqat~d pxopo~tlon. Ul ~e~t ~te~
werQ l~f~ open ~unoccllld~d~ and w~e rubbed an~ brush~d o~ at tim~ zero. ~on~roI powde~ ee we~e ~ehed at time 6 hc~ur~7 ~-rub~ed powds~ ~it~3~ w~ ubb~ ~t 6, 8, ~nd 24 hours~ R~adlng~ ~r~ ma~e a~ ~itne~ dic~e~
D~ta r~pr~3en~ pet~cerlt r~ading~ tzlk~n at r~ rubb~ ~lit@~l minu~ p~r~nt ~eadin~s tak~n ~t ~orr~pon~lng control glt~, :' .... .
~3~3 T_ Va3scon~trl~t~0n_ A-~e ~i ~
~A~
8 _24 32T~t~l FLUO~IN~NIDR Fo~uLATroN
Site~ Re~pontin~ ~%) ~7, ~ 81. 3 237 . 6 Inten~ity of Re3posa~ 75.0 29.229~2 133.4 Sit~ Re~pondla~ ~%) 87.5 6~.5~R.8 ~18.8 In~en8ity of ~bspon~e (X~ 72,9 20,R25.0 11~.7 Sitos Re~pondlng tX) 87.5 62.5~8.3 Z1~.a Int~nal~y of Reaponse t~) 66.7 25.022.9 114.6 Sitoo Re~pondin8 ~%) 93.8 75.081,3 250.1 Int~n~ity of Raoponse ~ 72.9 27.12~-2 129,2 ~ol e ~, Si~ea R~spondin~ (~) 75 . 0 81. 3~1. 3 237 . 6 In~n~ity o~ Ro~pon~ ~X) 58.3 ~9.2~9.Z 116.7 8i o~ Re~ponding ~2) ~3. ~ 62. S37 . S 193. ~
Int~nstty o~ Reopon~ (X) ~8,8 2S,012.5 l06.3 ~ite~ R2dpoading (~) ~3.8 68.868.8 231.4 Ine~n~ity o~ R~spon~0 (~) 7~,2 27.12~ 9.2 8lgeÆ Re~pondln~ ~X3 87 . 5 7~ . 0 87 . 5 250 . 0 Int~ll31ty o~ Rsspon~ 77,1 27.133.3 137.5 NGTE: ~o~ag~ ~o 3 ~ o~ ~o~olstu~baoe~ oln~ nt contsirl~n~ poly-~r po~d~ th ent~pped ~luocirlonlt~ ~t ind~cAeed proportiolt, or 3 21l~ Lide~ 0.0S~ ~luoclno~ld~ ol~t~an~. T~ lt~ w~ ~bb~d at tiD~ z~o, wa~he~ ~t tl~ 6 hours, ~t r~d ~t th~ tl~e~ dlcatetO
, ..
~3~
In an additional study, ~luoclnonlde wa~ di~olved in a ~0/70 p~opylene glycol/propylene carbQ~ats ~y9t~m and entrapp~d in the microspong~3 sponge entr~pm~n~ e ~em in a~cordance with th~ pre~en~ inven~iorl . The 5 degree of vasooons~rl~tion prod~e~ served ~ an indi-e~tor o~ ~h~ r~lea~e o~ the ~ort~costerold solukion from the micro~ponge entrap~ent ~y~tsm. Equal amount~
of tha micro~copio spong~ partlal~s wer~ ~lre~tly ap~
plled to ~man ~o~arm~, rubb~d gently, and ~ha exc~
powder brushed of~. On one Arm, no ~urther ~pplication or ~nlp~la~ion w~ made. On ~he o~her arm, ~he 31te of initial appllc~tlon wa~ qen~ly ~ubbe~ at 7, Z3, and 31 hours, but no additional product was added.
~a~ocon3trlc~10n re~pon~e~ were mea~ured and r~-cord~ ~t 8 t 24, and 32 hour~ and the re~ult~ are pre-sentad in Table 4~ ~h~ ln~r2~8e2 ~nd ontin~ed v~
con~tr~ction produ~ad in th~ arm that wa~ rubbed ~e~er-al time~ is deflnitive evlden~e of ~he demand and ~
~ained relea~e o~ the cortico~roid ~olutlon rom the micro~ponge entrapment sy~em.
~, . . . . . .
~3~3~
,.
20 ~ 3 ~ 2~ 33~
~ ~ '~ ~ ~ ~ o ~ ~ ~ ~ ~ ~ ~ ~ ~
z s ~ ; I ¦ ~ 3 c ; ~ 3 D ~ D ~ 3 ~ e . .
.
3~3~3~
.~ 25 H~llng ~ully de~crib~d khe pr~s~nt lnv~n~lon, it will be apparent ~rom the above d~cription that vari-ous modlf~tiOns irl the speci~ia compositior.~, proce-dure3, method~ ~nd proce~es ~ay bf3 made wi~hin th~
~cope o~ ~he inv~ant~ on. ~here~ore, the lnvention 1~
not in~ended to b~ liml~ed to the p~rticular cc: mpo i-tions, pro~e~3~s or m~thods excep~ a~ m~y ~e required hy t~e l~w~ul 8C:0p~ 0~ th~ following clalm~
,, ,
Claims (10)
1. A composition of matter comprising a steroid active ingredient solution absorbed within network of pores of a preformed porous polymer bead, said network of pores being substantially noncollap-sible upon removal of the solution,
2. A composition of matter comprising a steriod active ingredient solution absorbed within a network of pores of a preformed porous polymeric bead, said bead being dispersed in a medium substantially immiscible with the solution, and said network of pores being substantially non-collapsible upon removal of the solution.
3. A composition of matter comprising a steroid anti-inflammatory active ingredient solution absorbed within a network of pores of a preformed por-ous polymeric bead, said bead being dispersed in a medium substantially immiscible with the solution, and said network of pores being substantially non-collapsi-ble upon removal of the solution.
4. A composition as recited in Claim 3 wherein the steroid anti-inflammatory active ingredient is selected from the group consisting of fluocinonide, fluocinolone acetonide, triamcinolone, betamethasone valerate, timobesone acetate, hydrocortisone, hydro-cortisone acetate, triamcinolone, prednisolone, predni-solone acetate, dexamethasone, beclomethasone dipro-pionate, betamethasone dipropionate, betamethasone ben-zoate, clocortolone pivalate, halcinonide flumethasone pivalate and desonide.
5. A composition as recited in Claim 3 wherein the steroid anti-inflammatory active ingredient is fluocinonide.
6. A composition as recited in Claim 3 wherein the steroid anti-inflammatory active ingredient solution comprises a steroid anti-inflammatory active ingredient and percutaneous absorption enhancer select-ed from the group consisting of propylene glycol, pro-pylene carbonate, a mixture of propylene glycol and propylene carbonate, Azone, dimethylsulfoxide, dimeth-ylformamide, dimethylacetamide, diisopropyl adipate, isopropyl myristate, tetrahydrofuran, tetrahydrofur-furyl alcohol, glycerol and N-methyl-2-pyrrolidone.
7. A composition as recited in Claim 1 wherein the polymeric bead has a diameter from about 10 microns to about 100 microns and a calculated cross-linking density in excess of about 10%.
8. A composition as recited in Claim 7 wherein said calculated cross-linking density is be-tween about 20% and about 50%.
9. A composition as recited in Claim 1 wherein the polymeric bead is copolymerized from a comonomer pair selected from the group consisting of styrene and divinylbenzene, vinyl stearate and divinyl-benzene, and methyl methacrylate and ethylene glycol dimethacrylate.
10. A composition as recited in Claim 2 wherein the medium includes a component selected from the group consisting of petrolatum, polysiloxane, paraffin wax, mineral oil, beeswax, spermaceti, and fatty acids, alcohols and amides having from 10 to 22 carbon atoms, and mixtures of the foregoing components.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US84632186A | 1986-03-31 | 1986-03-31 | |
| US846,321 | 1986-03-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1303991C true CA1303991C (en) | 1992-06-23 |
Family
ID=25297555
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000533503A Expired - Lifetime CA1303991C (en) | 1986-03-31 | 1987-03-31 | Composition and method for delivering a steroid active ingredient |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1303991C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11213587B2 (en) | 2010-11-22 | 2022-01-04 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
| US11648256B2 (en) | 2015-06-18 | 2023-05-16 | Bausch Health Ireland Limited | Topical compositions and methods for treating psoriasis |
| US11839656B2 (en) | 2010-11-22 | 2023-12-12 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
-
1987
- 1987-03-31 CA CA000533503A patent/CA1303991C/en not_active Expired - Lifetime
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11213587B2 (en) | 2010-11-22 | 2022-01-04 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
| US11839656B2 (en) | 2010-11-22 | 2023-12-12 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
| US11957753B2 (en) | 2010-11-22 | 2024-04-16 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
| US11648256B2 (en) | 2015-06-18 | 2023-05-16 | Bausch Health Ireland Limited | Topical compositions and methods for treating psoriasis |
| US11679115B2 (en) | 2015-06-18 | 2023-06-20 | Bausch Health Ireland Limited | Topical compositions and methods for treating psoriasis |
| US11679116B2 (en) | 2015-06-18 | 2023-06-20 | Bausch Health Ireland Limited | Topical compositions and methods for treating psoriasis |
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