| US20110223255A1 | 2011-09-15 | |||
| US20100173005A1 | 2010-07-08 | |||
| US5540912A | 1996-07-30 | |||
| US20030134810A1 | 2003-07-17 |
| Ε ΙΜί: 1» A. o* d¾od for tre kg a pmkni t ecently ¾¾ mirgkally tret ted Mr reseetioa o ca c r mass, Use wseiinxl c ffi mis ; administering ¾ onnd'area that resulted fom e»cer resection roeedure with a a plurality »f ndcr^partkles enco assin one or more eaoeer treatment drugs or a plurality f mkr -partkles encompassing on or mo e und healing drup a8edkas»e»ts? wserela said, a plurality of lakro-parikles encompassing one or more cancer t eament dregs or me kaiMots are selectively leased for a firs e iod^ md wherein sold a late ali of miero~particie§ eaeensp smg. o«e or more wowed healing d.rug§ or medicaments are selectively released for a second period. 2, A. method for treating a patient who recently was- snrgkali treated for resection of a cancer mass as ecited in Claim % wherein said firs period dikes an inc e se physical si*e of the tnkro-partkles o iiidnee a edu ed rate of release of one or more drogs or medicaments. 3. A method for treating a patient who recently was surgically treated for resection of a cancer mass as recited m C irn .!., wherein .said first period ndlk.es increased tdoiecidar weight of the FLGA molecule to radnce a redocei rate of release of one or owe dru s or 4 A method lor treating a. p tien who recently was surgically ated for .resection, f a ea&eer mass, as recited hi £ im wherein said fi st period utilizes an. Increased rato of poJy!aefk add is polyglyeelie acid in a PLGA molecate to hid see a reduced rate of release of one or snore d oss or medkaineats. S.. A method for treating rpaiieni win recently was sorgieaMy treated for reseeiioo of a ca cer mass as recited is Claim .!> where said first e iod utik-es oae or taore miter ediings o» the micro-particle to ndlace a delayed release of one or more dru s or 6, A metho for treating a patient who recent!v e snr&ie Mv tr atd for reseetlo of a cancer mas as recited in Claim 1> wherein said seco d peiod ntilkes a decreased physical ske of the micro-particles to in uce a« iacreased rate of release of ooe or more drags or 7» A etltod for treating a patient wfca ecently was surgically treated for reseetloo of a cancer m ss as recited in Claim I, wherein said seeood period ¾itill¾ s a decreased •mokcaiar weight of the FLGA molecule to induce an Increased rate of release of one or more drugs or jaedkameRts. 8. A method for treating a patient who receatly w s- surgically treated for reseefioo of a cancer mass, as recited Claim U waereio said second period stilues a dec eased ratio of pohiaeie acid to polyglyeotk acid ia a FLO A molecule to induce aa increase rate of release of ne o more ttrogs or m ica nts, 9, A post-sargkal treafcaeat compound* sad compooud comprising: a plurality of micro-particles encompassing one or more cancer treatment drugs or medicaments; a: luraliy of niicr#*partlele$ encosnpasslog one or more - aad.heaiag drogs or me c nieEtsi wherein said plurality of aikro-partlcles ncompassing oao«r more cancer treatment drags or .medicaments has ¾ first released period; and where said plurality' of onerq-parficles encouipassing one Of miw wimmi he ling drags usedka seats km a s c nd released period, 10. A method for treating a patkat who recently was surgically treated for resection of a cancer mass as recited in Claim % wherein s d first period utilizes m increased physical size of the Micro-particles to induce a reduced rate of release of one or more drugs or medicaments. 11. A method for treating a paiieai who recently was surgically treated for resection of a cancer mass m recited in Claim w erein said first period atiliar.es an increased molecular weight of the FLGA laolecaie to Induce a reduced rate of release of one or more drags or o'.u'dieanse ts. 12» A osei¾ed for eating a patient woo recently was sorgfcsl! treated formection of a cancer mass, as recited in 'Claim' 9, ie ein said first period ati!kes a increased ratio of polylactk ad to pofyglycoiic acid in a M.GA molecule to induce a educe , a e of release of one or more drugs or medicaments* .13. A method o treating a patient who recently was surgically treated for .resection of a cancer mass as recite! m Claim % where said first period otilkes esse or more outer coatings .a the micro-particle t iodoee a delayed release of one or more drags or medlca meats. J.4. A method for treating a patien who recently was surgically treated for resection of a cancer mass as recited in Claim wherein said second period utilises a decreased physical size of the micro-particles to induce an increased rate of release of one or more dra s or ■m dkasn nts. » A met od for treating; a patient who recently was surgically treated for resection of a cancer mass as recited in Claim % wherein said second period utilises a decreased •molecular weigh of the PLG.A molecule to induce an increased rate of release of one or more drags or me ic ment . :4 A roited for tre i»g rpaiiem wis> recently was $«rgi s i ateci for resec&^ sfa caaeer mass, a reeked m CM % w&erelti said secoad |¼<r¾)d »{ila«s a decreased ratio of p lylacfic acid to poljgiyco!k aci m a FLGA molecule to induce aa increased rate «>f release of »»e or more 4mm o.r eilfc sM¾ ¾ |
USING STJSTAL EBAKD/O DELAYED RELEASE OF EBICA E T§
CO TAI ED IN MICRO-PAMTICLES
FIELD OF THE INVENTION
|0I| Tfee present inwatlon comprises a treatment, roc ss .following, cancer snrgery.. Mere specifically, the preserst. kiyeitiiffn eompn&s a ocal chesnotherap-y treatment process after surgery to pr vent d al caster recarre&ee using a sustained, controlled chemotherapeafic or biologic therapy r»g dliv ry system.
(02] Here a e fear major types of eaucer r tmen; 1) surgery 2} chemoth r py 3) radiation 4} biologic he apy. If the iimrnt appears to e coiifined ta : «¾ie area (localized -and not metasatic), surger ma be used to remove it al ng with an .nearby tissue that might coetatit ca.nce.roas cells. It I often difficult to predeermi e how large the snrgerkal resection will be, The surgeon generally makes that deferniiaatioo w en (s)he sees he extent of the cancer during the operational procedure. Surgery Is most sssccessftd when the cancer has not metastasized (spread to other organs). Surgery offers the greatest chance of enre or long ter.rs remssi n .for many type® of c»nee.r« However, even ate * snrgery, cancer y recur afer several years. This cancer recurrence may be d»e to some residual cancer cells hich were not removet! during the surgery. To- kill these residual, cancer cells, p tsurgc l Barfey e at, e o ie that j>o -sargieal . i thn therapy reduced the : risk xecB ren.e dwrfag lie 18 years after breast cancer surgey from 3S% to 133% mi reduced the risk of death imm breast eaacer item 252% to 21.4% ove the .first IS yean (Lmm * (2M !)).
C«rrea as oncologists in the 1LS> use t¾e radiati n thera y after hi geeo r (breast* conser ing surgery) as siaadard procedure. However, It Is ex ensive ($ ,100 -- ■ .12,000} ad cu¾»bersoi»e (4-5 weeks treament), in addition, there are side effects, i»d»dIog skm b»r»s and fatigue, Aefcs et ».!, ep ted tha syste de dH'^ lwrany alter sorgery led to higher rates of dsease-free mni »veralisnrv!val for w®t»es* with Isolated or e i nal cu rence ef breast cancer (2012€T C~ €E San Aat aio Breast Cancer S m osia^), However, systemic: eb oolKra y is expeofrec a d mi m&mfiilm all treated patients. Slodles roice stow that nearly 58% ef systemicall adminis red aditasel is excreted in the first day -and less tttaa 0,S% »fthe total dose r tSm locally available treat caacer wit k the |»»g (Sparrebeoitt et aX Aatkaacer Brags, 78 6 (1996)). To resell effective levels locally by systemic delivery, high doses are accessa y, which may lead o ncreased risk ofsystemk toxicity and morbidity, fBj Sustained and delayed release over several weeks- of anticance drog from a release, fo m ad lnistred alter surgery ould efihaacc their efficacy m killing resicnal caseer cells ifRotit caasing side effects or toxicity associated with the radiation therapy or systemic chemotherapy, Sastaiaed release form of aafkaaeer drug locally over several weeks would facilitate mni ensare the killing of residual cancer cells a different cell cycle age. One §>roMeni wills immediatel releasing an s tleaoeer dmg is that they are weraf!y «t~pro!ifer¾i ¾ΜΙ mm tafet i ' wim . h slia follo in mm& ' t zty * : 1¾ Isetll&g f-waaiads, iaeiuslkg ike mrni mml fey sirgkal r¾secftoi,Js a somal s p ams Hist hmih tfce jtctivatlea mil s$m r imt & of man ≠mki i wm dmVmg m&g i ^y m mim-y mats, $*mm t m aecretiaa, ¾p s .a ofeoMa ea., epffedlafaioe, OSMKI e ¾iraeii¾ tissue graauf aiioa sad reBiodsl g, BsririisiSM eaased by the addiion »f atiti-pro erattve dra such m astt~ca»cer drag caa kadi te c roate waaads thai are difficult to m&msge. Most ofsastaiaed release i g delivery syste s sfeow isx M hurst release y^ltam he first 24 ···· S Jioars followed hy m m& ttuiiomi stow release »f tlie taea smtated d ag. I ls Initial b»r$t release of anti-c&acer drag esay impair woir¾«I telog. A» idea! ajiticafteer sasiata k controlled release dra deliver s stem staM p m. the Mfomikg propertied
|04| L Smtmmd mui controlled rel ase oC anticancer drug ever 12 weeks
0S| 2. Reduced 24 ·- 48 ho»r iahial barst f anticancer drag
06| 3, Acc«leratfo.» of or not iahlMtiag wound feil.bg during the first 7 ~ Ml days 07 , Biodega able, eliminating the need tor sargkal em val.
|.88J A local anticancer drug delivery syst m «ssesslsg tie absve properties was developed mii escibed by ' CoIsoa et al, (Aeals of Sargk&l Oncolegy, 1:283-1.213 (2018); US ≠Tt,m$; §,3332 §,338, 92, m. , Fublkatioa:: US
241 /1 ) 1 59:54 and 2014/027148 ). Tilts s stem used a ftMt or mkro-partkle forsta
fch consiss of polyCglyceroI M«M¾ ¾;ir;ite~c:s~i~eaprolacfoi.») and pacUiaxel, The paditai;l~¾aded polyme fi!ot as Implante , cm t&e iforsmai of mice after e removal of prims -r -care . The pt ¾¾Mil¾a ed film prevented local eaoee ecurrence m 13,3% of mke compared with i2S¾ m ' i® ®&Mm,. These i ii caim chat beir lymer film avoids the nitial burst release of paelliaxel y fa.aet» »¾l¾¾to8 of tlte hydrox ! gronp I» glycerol wiifc hydrophobic siearic add. Ho weve, the polymer deveoped sod ssecl in their system is dificelt is sy hesfee a d ins possesses less com.merd.aI value. In addition, the polymer is a novel orm. Regoiaiory authorities woai require proof ef safety before a vn it for «.se in meilieal applieati.o.».t Bretn et al. (IIS 2¾l.2 .i.21S18 At) desc ibed two •methods to achieve tie above id l properties; 1) desgning and preparing artcls wMclvdoooi release antcancer drugs for a roximael 2 ■ ·-· 3 weeks and
administering them mmediately after s&r r or 2} o odmio lo particles which releas -a.atica.8eer drag Immediately nntil 2 - 3 weeks- after snrgery. Method 1} is dffieolt to achieve at a commercial t aoaiacorlog scale; the aothors id sot clearly describe how to ima such particles. Method 2} quires injection by a syringe which will be pain»! to patients. In additon, the injection may net distribute particles In e enire area where there mm be resldnal tumor cells, Ognra et at (Snrgery, 66-71 (2086)} applied a fixture of genidta ne (anticancer drag) a d fibrin lue (biocompatible hemostat) to the toll of the pancreas o nude mice whkh were mjeded wlth ' SUIT~2 ' homan pancreatic -cells. This local drag delivery system aimed to demonstrate the raldbifkm of proliferation of resldnal pancreatic cancer cells. GL!ADEL® wafer Is the most eI~kao o local anticancer dra delivery s sem mannfactnred nd commercialized by MGI Pharma. The GLIABEL® wafer m de .of a biodegradable pof »«lrdride delivers an anticancer irag (ear sosioe):. w pteeed ms to the & r ns, fm freaiiag rs¾llpas¾t giioMastoma &tktits ¾f¼r su g y, It improv s the survival ae of
teated »tig«t$ modestly i ifte quality of life com are, to systemic
.chemot er&gi * H we er, th d ag deliver system does i mkhr m mi
lieafmg of ike resected ar s * Therefore, there is still a seed for a bette dreg
delivery system to educe the likelihood of eascer recurrence ithout nhibiting the wotmd healin .
[ { f Tie resent ff¾ rdl« eoisl s o dffl!eeat t Mier -particle te d -oh biodegradable polyester:
P0| 1) a first plurality ®f sstlcro- arilck (I) coiitaimag anticancer drag wit out the imtml burst release; an
f i l f 2} a secon p n¾Jiry of micro-particle (II) releasing. wo».»d ealhig drags.
112 J The first, lurality at mk ~pmikl (I) releases aatfcaacer d ug ever 12 weeks ithoet m imt l fetirsf release. The second plurality of micro-particle (II) releases wetind healing ir gs ¾l& 7-10 days aeeelesle wo^M healing. Mil preferred e¾ fel sj a, the present M aiioe otilfees oMaeiie gtyeolfc add co ol mer (PLGA) eo t& njttg
a&tkancer drag such m seitaxe! for the f t ls slliy of o¾kro » parliele (If ? an osmd healing rags such as bnrneel and issiatl sabgalkte for tie secosid phirallty ©f saicro- particle (II). AH of the eo»ipo»e»t$ I.» the preferred embo iment Including FLGA, paciteei * or&e ¾»d &i$t$iit|t .ijgbg$H$t@ a e ¾e.€ pf¾ - 8« . >p i ¾^ ' fey lie ti,S, & tod (I) imi (II) m ikm resent Ι«ν«86β» esi« e raked before a lyng to tfee estitre area, from »icb. the rum r
drugs before the so? gkal woa.«d ¾ dosed
DESCRIPTION OF THE PREFERRED E BOfMEME Γ3
MiCEO-MTIC I
|1 ' 3| kra-partlete used herein r fe to srtkfe iiavlsg s es between 1 μ*& sid 580 ro ami Imhuh mM othe pa cles * Miero- inkies c m osed of dr»g$ or *¥*e teai»es*$ m& l me s are mmtmh- used 8$ a $«t»i»ed»C8»tr Iled release drug delivery system. Microcapsules generally a a drag core coated with $\ polymer Mm and saay be s herical or Bois » $p¾erkaI m
shape. I«t contrast, microspheres ha e dregs dispersed eveaiy I» polymer a»d are s erical in s a e,
POLYMER
11 | Mkro«p¾riefe in ilm veutloo eoosist of Msdegradalik eiytii Mk¾oeer drag .or woassd feeAg drugs/med!eaS-eafc. B degradable p lyme s ¾re defined
polymers that are degradsbk k vivo, iher ¾yi«aiealK' o ftoo-c&vs maic&O , to p oduc - sii«.¾~ro hy-pre octs. Biodegad ble -polym s have fte oiste i¾erea$i¾gly of drag d livery.
Biodegradable pol m s ca« e fbrmslafecf ltfc drags.- to form a d^¾¾g delivery s stem feseh cm provide sustained and .o»troMed .release of ¾lr¾sgs aver s weeks or Toootte., S¾ee th d a delivery system feed oa odegra a e -polymers d g ades completely over tfcee* it is liot B r y to reiaove it fey i sargkal ocedure after implaitttag or
administratioo, Biodegradable olymers cm be classified into aattsral biodegradable polymers or synhetic biodegradable olymers depeodiag on fhesr sou cs, Nator&l fei«di¾adabfe polymers hidade gelatia* albamia* eallagea* alginae, -ehifosaa^ delyadxed celltdose, starch, feyalBronk add and dextran. Syn t¾etk biodegradable polyroers iada.de pol estes^. polyaretfeaness poly ios aiise^ poiyanhydrldess po!yearooaat s a¾S pol stemmid . Polyesters k¾e!«de po!yteclie p&lyglycolk (FGA), polyeaproIacfOHe (P€L) sad their copolymers fedadia w¾ll~k»ow» olyladk gycolk acid ' (PLGA. Tb ' eir safety and asef«ines$ as a drag delivery system are well studied and accepted fry regiiiatsrrv authorities worldwide iodtidiag the U.S. W A, I» one embodiment, tie present invention wses polyesters. In a preferred emboditaeott the present invention oses L A, ¾ copolymer of PLA sod PGA, Polyesters overall possess ideal physical aad cbemkal properties providing ease to pocess, aptintnm drag release profile- over days, weeks or moolrs and los!-texk y-prodiiefe after degra ati n
¾EII ^o II ) K:¾. E^1 iS| Anticancer drags can fee classified ioio cheiaottierapealic drags aad biological drags. Chemotherapentic drugs e&n he furthe classified by their mode of acti hj
fllf 3) aatimkrotuble;
|T9J 4) tO|M¼dse e iahi itioaj sad
(20J 5} cytotoxic aaiMotk.
Alkyiatiag ageats include aitregea must r s, Mro$o®reas, fi ilas, ax dlfies, elsp sad Its deivat s, ami aaa-classicaj. akylatlag a ents sach as oearh&xiae a»d hex8meife l¾¾eki«i»e. A»!i«tetal>ol¾M iaciade «&~I¾l ¾s fiaoo v aM es,
de xyitacetosid aaa!ognes aad tfeiopaoaes. Aatmikrotabale a «t$ isciade ^i ca slkfcleids asd leases ladadia cllta el
\22\ Topo.bomera$« mhibftars iadade irs ecaa, -tapetec.a» ««d other a».a!»g««&
C^ ie aatibloiks iaclade osorafekia,. daanorahida, eoaiycia sad other aaalagaes. Missi of biological aatfcaaeer drags try to eabaace the arent's aaiaral iasamae responses agwissi canc r ceils.
|23| CiiiTe& moaoeloaai a ib dies, iaterleaMas. and iaterferst¾s are ypes af fetetegkal assl- tscer drag cammoal ased. to treat varsoas e e s. oaodomd antibody- based biological aattcaseer d e s iaclade Il.e.reptla(t\ t»xa»% Avasffe® a ad oili ageats. As s new class of aati-eaacer drugs, saono aaal aatibedies can be eoajagated will ebemotaerapeatk ags * Maaodoaal aatifcodies cm be desigaed la target turner cells specifically. The ajoaoclaaal aati adies conjagafed with cbemotherapeatk drugs cm ke the co.»j«gat<?-d c-hfcmatfeeap-eatk drags. sad deliver theaj specifically ts the caaser c ls hat
S ■ m% Mis r celts, Tim limjt.ii ie damage !».sw¾al ceils, B-xs ' si lfes of &ese types of Mtii odm htehide. hr$8tah¾8h ^ei ls (Ai«etr£s¾ aai «d rmta M$b ' em¼«ia
(Kadeyta^), The current ta y ertfia** us s my m of ibe a v da s -or a eom kaiioa of severs! d.mg$.1.» s¾ ferred emhod tse&t, aatkaa&e dr&g eaea ulate it ffifcro-p rftele ) is ptdiissei
\24\ Wm A healteg drugs ca be classified teto small molecule dr»p such as meiwterpeit -basecl or m »eter e» W- ased drugs ami biological d ugs sucb p elet- derived growth facto f?i>GF} o other growtb factors. The «*e»oie j?««e- 8Sed ar i¾OB ei*$iea id»b $ed drags ladade baraeat, tbysttol, ge io, » er Iae I aad ΟΜΙΙΙ , To eohaaee woisod al!».g* other synergsic coittponeat s«eh-aS lsn.iat¾ satigaltste n be ee«bio«i with tlw osoo r eae-b e d ug, Splfeegfc® e oslsfe of fearaeiel m . bJshiuth wh&tz mil is a wo».»*i b*alag -product a proved by the U.S. FDA ia 2804 m oiament fo m (US #&232 > 34i), la ¾ preferred e»*bod »e»t, tbe res n i«venticia ases a combination of horoeol sad hisrautb subgaliate as wOisn<i heallag drags.
IICIFIE TS
|2S| Miav ar!fcles hi tbe presses* ia?eatio» *aay also eoataia o» or mo e
pharmaceutically acceptable additives. The t rm "additive is all euaspoueats coafalaed ia micro-particles other tfeaa drags or polymer sad ia.clu.des, bat not limited to, bof&rs, preservatives aat antimicrobials. It can also iudude bydropbd.k materials saeb as po!yeihytese glyco (PEG) or pal via lgtyrroiidoae (f VP) whic CM accelerate tbe o egradat u uf uicro- &rtteles. MI€ )~MIICLE; FA EICA ' D:
[Mf Mkro-partfcles m the p se laveation e¾¾ fee pre ' par I by mieiwaca sal iat*, spray dry g, recpitaties, hat .melt mkroe»c p$tilatie.a ¾ co-extusion, predsiea particle fabrication (FFF) or other fabrication techniques, Mkroeacapstilatlosi techskpes use sin le, do ble er m lti le «»mlsfen rocess in coni iaatl n with solvea removal step $\w evapar&tioa, e&traetkm or c0»cer a*ea ste , Tiiey are the m«st ce»m«>.aly used tedinkpe$ o p e a e aikro-partkles. The above tecliak es incladisg the
i^lc 9e« a $al i !8 ' t€hiti .»^ : €¾P fee «sei far water sil¾s¾sle ' d a * or aak solvent #i abie dr«g mnl soli powder tfriig. Polyesters ega be preeessed ifb .my aite afibe ibove tee¾ak|u«$..
P?| iero-partkfe (I) caasls!s of polyester wl aa eaaeer drag aad can e r a ed with assy oae efthe teea ' aM i s dscib d la the preveas- seetost. Mkra-partkle (I) degrad s slower mi ikm releases the caiitai&ed drag toage than i crs-partkle (II), la a preferred em odiment, the preseat uive»tio» ases PL€*A> Drag release .rate f' m PLGA. mkro-partfcks caa fee controlled by adjasfiag a aaia er of pataaseters swcb as 1) ratio between polylaetk acid (PL A) a» potyglycatk add (f€A), 2) melecnlar weight and 3) sixe of aiicro-partkk. la PLGA» paylaeiic add is m re fey<lroph«bk compared i« pelyglycolk ¾e a.»d sabse tieatly hyd olyw ie., degrades) sla er. for ex m le, PLGA Sf SC (PLA;P€¾) ahlfe s a fatter d^r¾dat$o» : ' P ' GA 75;25 im t¾ p eferential degr daiiop of glyedk add opo ti n if- two olymes have file mrn siRfe' ar weights, PLC A itft: higher molecular weight x ibits a slower degrad ion rate h n FLGA with lower ' *»elee«lar weight. Moieei ar weight has a di ect- fel k sMp with the poiy«ter chaia $i«e. Higher »iolec»lar weight PLGA. has Imager lymer ehaio a»d re¾aire« More lme to degrade thai* lower molecular weight ?L A. in add oa, as increase la aioleeaiar weight decreases drag tJiffasioa rate aad therefoe drag release rate. The s e of miero-p&rticie also affects the rate of drug .elease, Asr the si¾e of * cr«~ artkl« decreases* e ati of sari tee area to vohmie of the aiiero-parfieie inceass- Tfeits» for a iven rate of drag •dtlfastoiis the rate of dreg . release irom the imero-partk!e wll ke ess with dee reasisg
q«kke.r m to fh s-horter dist&aee from the sarface te the center of the ffikr - &rkie. 2S| The delivered PLGA atsero- artkle (I) degrades aad releases anticancer dra over 12 weeks to the caaeer removed area aad kll a»y residual cancer cells. ost
cbemoth rapeiitic drugs work by isapamag mitosis (cell divisloa). Most of caaeer cells exhibit cell cycles «i everal days la several weeks. Therefore effective d ag delivery system sfcotfld release aaiieaaeer drug over a loa period (>4 weeks) to avoid the esca e of eaacer cells which m y become a source of eaaeer recurrence. Miero- artiek (I) la the preset* t i»ve»tio« ca.a he prepared with PLGA I.) a nortioa of FLA e «al to or greater thaa 51%, t) molecular weight (M ) > 35ΛΗ) aad 3} mkro~t>artkle s&e larger thas 1 ftm< Preferably the mm of mkro-partide (I) is larger than 50 pm. Typks! composition of afcro~part£cle$ (!) i» i is i¾w o¾ s 6 - 95% of LGA d- 5 - 48% of a¾*iiC r
|2
P0| icro~parfkte (I) ia ths iavenfiaa cm be coated with a biodegradable |*alya*er to ' red&ee be imtmi a it release ofaatka eer dreg, I¾e c tag bladegradabte- .pelymer cas be tie mi olyme ased. I» mkr c^ gr&le (I) or dtfi¾r««t eiy»i€r,€«at¾¾g 0f¼ko~ particle (I) eaa be done fey v».r¾».s meho s mm m a caadag method through i¾e phase se aration ef mating olym oa tie surface of FLGA ndem-partkies asiag e*»u ®a » solvent evaporation atethod (H. Takabe et al, Fharma«ology & Fharaaacy, 578-583 (20S4» »r a doablc-walkd -saicro-partide fabricaiioa method (Q. X» et »L Blo.a? erial&, 3982-3911 \ MICRO-PARTICLE (K 3:2| Mkro"psrtlcle (II) consists of polyester »«d woaiHi bealtag d»gs aad ' can be prepared wih any one of the t chnques described hi the re ious seetioa, icra- arekle (II) degades muc taster than micro-particle (I) sad releases oaa bealiag d ags durijtg the first 7 - 10 days, !a a preferred eatbodiais , he present Isveatian ases FLGA, Micro- particle (II) ca» be p epaed ith FLGA 1) LA: PGA $8:5 ( 12) .«iol.ec«la:r weight (M ) < 35,ίΜΜ! Mi! 3} dero-psri ! m < 50% .of ¾ " &Ie (I) s& f k #ly tfe m »f slerc |a.iee,(il) k smalle Hum. SI ) »L Tvpk l c mposltksi f imero- & fkl ( ) m tills raweatkHs Is - 95% of PLGA and 5 - 48% of eo$ih½ed winmd h^alk togs, in one mfeodime * mkro- arke (f) eo aios ¾«*«eo_ ( ¾w*6ierpfc8.«! s CIS 5%) md bkm ih safegail e {!. - 111%) as oasd healag drugs * S«lb»gi»€> eoosktio of ' both d regs was app oved by tl IKS, FDA la 2i¾M as as kteieat farm lor dally a plic ti n aod commer alise the 11,8» It is a aatageoHS of «sh*g the d gs a p ved by tke 1 S, FDA * In a refe ed e^bts$h*se»? # .mkro^sa tkk (II) can be epa ed wii t¾ s¾me cempositi&a of ¾oroeol (§,?%} and ismuth. ssh Bate (4,5%) osed Sulfee ia^
MIC¾l)"FA¾TICIfJ lI.J:yER¥
|33| Ceated-t»kHHp¾ri:kle (Ϊ) m$ mknvpar tde (II) are raked* at a ratio of «Mted- micro-particle If) to micro-partde (II) less ih IKS mul preferably 0,25 to make sure that the release ammmt of wo«»<J healing drags sur asses that of anticancer drug di ag Use fim 7 - 1 da s. The ewibmed imero-partkes (I) and (II) skipkl be administered tt«jf«rmJ to the ent e eaoeer remov d a ea t avoid the overdose of some area. Tie o¾∞«oi of delivered ¾ikr8~par tides shoul ht ietermnmi and adjused depesidtag on !ie si¾e of oe cancer removed ' area.
34| kro~par¾te p) $m « prepared by «¾ « »-w¾te gm lslosi 8.a¾ solvent eva of&i ii tmrns * Brkfty, .p lted |S0 m )js Jissokfcit I». a kfeo ofPLfiA (f,$ 75? 25; MM ~!98#08} i» S mL of dkMor metb» The gmk solution, is aided irto 20 mh of 1¾ polyvkyl alcohol (FVA) &¾ eo salAa, FVA is osed to ahdke lie emti ficid kr - particles aad prevent icro-partkle feioa urlag the metekm proc ss. The .resaitiag solution Is rapidly taaogeasteed oslag a fK>«>geoi¾er for M sec, " ike sl¾e of miero-partkles caa be co troll d by the speed of the hotaogeiti%er. ¾ sak re is then diluted with 0,1% FVA with a filial votane of 500 mL, ud st ed at 1CMI0 sa at mm te∞gter»tart sitd
collected by eeirrifef ¾fk» *®ύ washed with- cold d tailed The res.altiftg aiic o- aricles are h «. f o¾e» usiog dry fee tod dried ¾ a jyopl li¾er.
|35| The fyophiiized miero~pa.rti€le (L 1 g) as prepared above is dispersed in 1.50 mh of a 0.1% PV ' A aqueous solotloa, so the resoit.iog disperson is ad ed to 2 mh of a PLC* A eeatiag so iea eoiaslstkg of lOlteig .of F GA dissolved i» 2 ML of acetone. The mixture is fell stirred for 3 ¾ -at 40 °C» He mkro- artkle (¾ cooted with PLGA washed with cold de.k.oked water ul lyopbl!ked. The fyopbilked mlero-pa.rlicle (I) is stored at 4 <f C, 36| PL€ : A ¾¾5 M = ::: -!5 > 00) w the form i>fgrt«« M * ld «f tower thm
thk powder mim (10 g), is *dded find? whwmi bwnwl (79 sag; melting ¾ « 2§i ·<¾ Msmatfc $ahgalf»ie(45§ m melting point == 223 f €) and other additives web as boric add as s baffer and esKeaesislfesisffiide (mettiftg oia ;;;; 151 '*€) m antimcrobial The ave a e grain sk« of two orssgs and two additives is approximately 10 μιη. ' Th resaMag .mi u e is homoge.»i¾ed in- a mill at room tem er u e, The homogenked nmiare is thm extruded at 88 -··- 100 ft C wife a diam ter of approsiffia tely 1 J mm * The e aiaed rods are left to cool at resm iemper»t«re, eat lato s all iec s aad Smally milled it » 30 * . After sieving, mkr«» particle (M) wltb an average sfe of or less bat larger h n 1 es is collect d, the wtt!tlfig jiskd- (li) ft M at * i C>
FINAL FORMULATION 37| Miero-partiele {I, ChS g) ami Micre-pa.rtide (II, 2 g) are mixed thoroughly and the resalting tmxtare is applied to the ares from which the tisamr was removed.