RESEARCH ARTICLE
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Rese oi -Type Subcu aneous Implan able De ices
Con aining Po ous Ra e Con olling Memb anes o
Sus ained Deli e y o Rispe idone
Linlin Li, Andi Dian Pe mana,* Juan Domínguez-Robles,* Muh Nu Ami ,
Habibie Habibie, Qoni a Ku nia Anjani, Li Zhao, Na alia Mo eno-Cas ellanos,
Ryan F Donnelly, and Eneko La añe a*
Implan able d ug deli e y sys ems a e c ucial o achie ing sus ained deli e y
o ac i e compounds o specific si es o sys emic ci cula ion. In his s udy, a
no el ese oi - ype implan combining a biodeg adable a e-con olling
memb ane wi h a d ug-con aining co e p epa ed using di ec comp ession
echniques is de eloped. The memb ane is composed o poly(cap olac one)
(PCL), and ispe idone (RIS) se ed as he model d ug. Cha ac e iza ion o
bo h memb anes and di ec comp essed pelle s includes ha dness es ing,
op ical cohe ence omog aphy, me cu y in usion po osime y, and su ace
mo phology obse a ion. In i o elease s udies o RIS e eal ha highe d ug
loading in he pelle s ex ended- elease du a ion up o 70 days when
inco po a ed in o memb anes wi h ou laye s. Inc easing he numbe o
memb ane laye s slows he elease a e u he , anging om 70 o 170 days
depending on memb ane hickness. Biocompa ibili y s udies demons a e
ha hese implan able de ices a e non- oxic and biocompa ible wi h cells in
i o. In i o s udies conduc in male Wis a a s demons a e sus ained
elease o RIS, wi h plasma le els showing a significan inc ease
pos -implan a ion a a ela i ely cons an a e o up o 49 days. These esul s
indica e ha he de eloped implan s ha e he po en ial o p o ide long-ac ing
d ug deli e y o he sys emic ci cula ion.
L. Li, Q. K. Anjani, L. Zhao, R. F Donnelly, E. La añe a
School o Pha macy
Queen’s Uni e si y Bel as
Lisbu n Road 97, Bel as BT9 7BL, UK
E-mail: [email p o ec ed]
The ORCID iden ifica ion numbe (s) o he au ho (s) o his a icle
can be ound unde h ps://doi.o g/10.1002/adhm.202403689
© 2025 The Au ho (s). Ad anced Heal hca e Ma e ials published by
Wiley-VCH GmbH. This is an open access a icle unde he e ms o he
C ea i e Commons A ibu ion License, which pe mi s use, dis ibu ion
and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly
ci ed.
DOI: 10.1002/adhm.202403689
1. In oduc ion
Implan able d ug deli e y sys ems (IDDS)
a e ypically medical de ices designed o
deli e d ugs o specific si es o ac ion o
sys emic ci cula ion in a sus ained way.[1]
Deansby and Pa kes fi s applied his idea
o IDDS in p ac ice in 1938 when hey im-
plan ed comp essed pelle s o c ys alline es-
one subcu aneously o in es iga e hei in-
fluence in animal models.[2]IDDS, as a
long-ac ing deli e y s a egy, offe s many
ad an ages. I allows a ge ed and localized
d ug deli e y and can also bypass fi s -pass
me abolism and deg ada ion in he s om-
ach compa ed o o al deli e y sys ems. This
leads o as e d ug elease and lowe con-
cen a ions o d ug equi ed o achie e he -
apeu ic effec . The e o e, i migh po en-
ially educe side effec s and imp o e pa-
ien compliance.[3]Al hough su gical p o-
cedu es a e equi ed o ini ia e he apy, he
long-ac ing deli e y anging om se e al
weeks o mon hs, o e en a yea , may ou -
weigh his disad an age.[3]
I is difficul o gi e a classifica ion o IDDS because o se -
e al excep ions and hyb ids which may belong o mul iple ca e-
go ies. Biodeg adable implan s ha e mo e ad an ages han o he
A. D. Pe mana, M. N. Ami , H. Habibie
Facul y o Pha macy
Hasanuddin Uni e si y
Makassa 90245, Indonesia
E-mail: [email p o ec ed]
J. Domínguez-Robles
Depa men o Pha macy and Pha maceu ical Technology
Facul y o Pha macy
Uni e si y o Se ille
Se ille 41012, Spain
E-mail: [email p o ec ed]
N. Mo eno-Cas ellanos
CICTA
Depa men o Basic Sciences
Medicine School
Heal h Facul y
Uni e sidad Indus ial de San ande
C a 27 calle 9, Buca amanga 680002, Colombia
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ca ego ies because he polyme s used a e biodeg adable and bio-
compa ible, which gua an ees sa e abso p ion o exc e ion om
he body. Mo eo e , he su gical p ocedu e o emo e he implan
is no equi ed, which can also po en ially imp o e pa ien com-
pliance. Mos biodeg adable implan able de ices a e made om
a mix u e o polyme and d ug. A e implan a ion, he d ug will
be eleased wi h he deg ada ion o he polyme .[4]The elease
a e can be affec ed by diffe en ac o s, such as he deg ada ion
a e o diffe en polyme s in i o, he d ug loading, and he solu-
bili y and pe meabili y o he d ug.[4]By changing hese ac o s,
he implan can be designed wi h diffe en p ede e mined elease
a es. The polyme s used o ab ica e biodeg adable implan able
de ices a e mos ly he moplas ic alipha ic polyes e s such as
poly(lac ic acid) (PLA), poly(glycolic acid) (PGA), poly(lac ic-co-
glycolic acid) (PLGA), and poly(cap olac one) (PCL). Es e , amide,
and anhyd ide bonds a e labile bonds ha can be hyd olyzed o
deg aded by enzymes con ained in hese polyme s. These poly-
me s ha e been ex ensi ely esea ched due o hei ad an ageous
ai s including biodeg adabili y, biocompa ibili y, and mechani-
cal s eng h.[5]
PCL has been one o he mos commonly used biodeg ad-
able polyme s in IDDS because o i s biocompa ibili y, biodeg ad-
abili y, lack o oxici y, and compa a i ely inexpensi e p ice.[6]
I has become an FDA-app o ed polyme ha can be used in
he ab ica ion o medical de ices.[7]Fo example, i has been
used in a long- e m con acep i e de ice Cap ono con aining
le ono ges el.[8]The deg ada ion ime o PCL is longe han
o he polyme s such as PLA, PGA, and PLGA, anging om se -
e al mon hs o yea s. The deg aded p oduc s can ei he be me-
abolized in he ica boxylic acid cycle o exc e ed h ough he
kidney.[9]
A po en ial use o biodeg adable IDDS is he ea men o
ch onic men al illness as a sus ained pha macological ea -
men is needed. The e a e many injec able o mula ions ha
p o ide sus ained d ug deli e y o schizoph enia ea men .[10]
Howe e , he use o solid implan s could be used o ex end
he du a ion o he ea men . To da e, a subcu aneous implan
named DLP-114 used o ea schizoph enia is in phase II clin-
ical ials.[11]This IDDS is de eloped by Delpo (Delpo Inc.,
San F ancisco, CA, USA) using P ozo TM echnology.[12]Asmall
cylind ical ese oi wi h memb anes a bo h ends is used as
a ca ie o load ispe idone (RIS), an an ipsycho ic d ug, and
some excipien s, which can main ain he acidic en i onmen and
hen imp o e he solubili y o he d ug.[12]The Phase I ials ha e
shown ha i can main ain cons an plasma le els wi h li le fluc-
ua ion o se e al mon hs and dis ibu e he medicine in a ze o-
o de manne .[11]Meanwhile, a subcu aneous RIS implan was
de eloped and applied in adul pa ien s wi h schizoph enia o as-
sess i s pha macokine ics. This RIS implan achie ed he apeu-
ic le els wi hin a ound 2 days a e implan a ion and eleased
o 6 mon hs a a cons an a e. Phase II and III s udies a e cu -
en ly being conduc ed o assess he sa e y and efficacy o RIS
implan s.[13]
In his s udy a simple me hod o de elop ese oi - ype im-
plan s combining a biodeg adable a e-con olling memb ane
and a d ug-con aining co e p epa ed by di ec comp ession o
pha ma excipien s and RIS. Di ec comp ession is he me hod
using comp ession o p oduce solid dosage o ms om he blend
o ing edien s, which has ad an ages such as low cos and sim-
ple ope a ion.[14]The aim o his wo k was o design and de elop
RIS implan able de ices o use wi h PCL. PCL films and di ec ly
comp essed RIS pelle s we e ab ica ed sepa a ely and hen in-
co po a ed. Following hese s eps, a se ies o cha ac e iza ions,
in i o elease s udies, and in i o biocompa ibili y s udies we e
pe o med o selec he mos app op ia e o mula ion, which can
p o ide sus ained d ug elease and hen be applied o he animal
s udy.
2. Resul s and Discussion
2.1. Fab ica ion and Cha ac e iza ion o Di ec ly Comp essed RIS
Pelle s
Di ec comp ession is a manu ac u ing p ocess ha p oduces
solid dosage o ms om a mix u e o ac i e ing edien s and
excipien s.[14]Due o he ad an ages o low cos , sho e p ocess-
ing ime, and simple ope a ion, as well as he absence o he
need o hea and/o sol en s, i is p e e ed as he ab ica ion
me hod o able s o pelle s.[15]Besides, i is he me hod com-
monly used in he pha maceu ical indus y, hus scaling i up
will be simple.[16]
In his case, a small punch and die sys em (3 mm) was used
o p epa e he di ec ly comp essed pelle s using a labo a o y hy-
d aulic p ess and a o ce o 1 on applied o 20 s. These con-
di ions a e like he ones desc ibed p e iously o di ec ly com-
p essed able manu ac u ing.
As de ailed in Table 1, o mula ion R100 could no be o med,
as he 100% RIS composi ion o he o mula ion adhe ed o he
die and could no be emo ed. Fo well- o med and consis en ly
di ec ly comp essed pelle p epa a ion, he use o sui able excipi-
en s is i al. In his case, poly(e hyelene glycol), wi h a molecula
weigh o 8000 Da (PEG 8000), and Hyd oxyp opyl 𝛽-cyclodex in
(HP-𝛽CD) we e used. PEG 8000, plays se e al i al oles in pha -
maceu ical o mula ions including solubilizing agen , ma ix o -
me , lub ican , plas icize , and ehicle o d ug deli e y, due o i s
biocompa ibili y, non- oxici y, and egula o y accep ance.[17]HP-
𝛽CD, a cyclic oligosaccha ide de i a i e, is also widely used as an
excipien in pha maceu ical o mula ions. Some o he unc ions
o HP-𝛽CD as an excipien include a solubilizing agen , s abilize ,
pe mea ion enhance , and compa ibili y agen .[18]As shown in
Table 1, fi e ypes o pelle s ha e been ab ica ed, and mos o
he esul an pelle s we e obus unde isual inspec ion. In his
case, o mula ions R40P60, R50P50, R60P40, and R60C40 we e
selec ed o e alua e he influence o d ug loading and he ype o
excipien in he d ug elease kine ics.
Di ec ly comp essed o mula ions ha e been e alua ed be o e
o p epa e implan s o sus ained d ug elease.[19]In hese s ud-
ies, he excipien s selec ed o p epa e he di ec ly comp essed
pelle s we e NaCl and poly( inyl py olidone). In hese s udies,
he me hod p oposed was simila o he one de eloped he e.
D ugs we e combined wi h excipien s and subsequen ly com-
p essed. Al e na i ely, o he au ho s ied a combined app oach
ha equi es he combina ion o he d ug wi h a he moplas-
ic, such as poly(lac ide-co-glycolide), ia comp ession/ he mal
p ocessing.[20]The di ec comp ession me hod used in he
p esen wo k is scalable and does no equi e he use o empe -
a u e ha could lead o he deg ada ion o he d ug ca go du ing
manu ac u ing.
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Table 1. Summa y o appea ance o di ec ly comp essed pelle s con aining RIS.
Fo mula ion Mo phology Obse a ion
R40P60 •Well o med
•Robus
R50P50 •Well o med
•Robus
R60P40 •Well o med
•Robus
R75P25 •Fo med wi h a ough su ace
•Pa o he o mula ion s icked o he die, made i
ha d o emo e in ac
R100 N/A •Did no o m well
• he o mula ion s icked o he die, made i ha d o
emo e in ac
R60C40 •Well o med
•Robus
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Table 2. Response alues o pelle s con aining RIS. (means ±s.d., n=5).
Fo mula ion Ha dness [N]
R40P60 38.2 ±9.31
R50P50 30.6 ±6.35
R60P40 28.8 ±8.67
R60C40 30.8 ±6.42
The ha dness o he esul ing pelle s was e alua ed. The pu -
pose o es ing he ha dness o pelle s is o e alua e he maximum
o ce needed o ac u e a pelle . Ha dness plays an impo an
ole in u he assembly p ocesses and in ansi . Acco ding o
he esul s lis ed in Table 2., all pelle s wi h diffe en composi-
ions pe o med well, wi h no significan diffe ence in ha dness
(p>0.05) obse ed. These ha dness esul s a e in line wi h p e-
iously epo ed di ec ly comp essed pelle s p epa ed wi h pha -
maceu ical excipien s such as mic oc ys alline cellulose.[21]Ac-
co dingly, he ob ained pelle s could be handled app op ia ely.
Highe ha dness alues will make he pelle disagg ega ion ex-
emely slow impac ing he amoun o d ug eleases om he
implan s.[22]This is an impo an pa ame e as he e is a bal-
ance be ween elease du a ion and he amoun o d ug elease
o achie e he apeu ic ou comes.
2.2. Fab ica ion o PCL Films
PCL-based memb anes we e p epa ed by coa ing a o a y me al
od using PCL solu ions in dichlo ome hane (DCM) as desc ibed
in he Expe imen al Sec ion. Se e al cycles o cas ing we e e-
qui ed o achie e sui able memb ane hickness. To de e mine
a sui able composi ion and concen a ion o PCL film, h ee
diffe en concen a ions o PCL solu ion in DCM we e used o
ab ica e he PCL films. As shown in Figu e 1a, films ab ica ed
wi h a 20% PCL solu ion we e o med. I is wo h no ing ha
due o he hin hickness o he film, i is no sufficien ly ha d o
esis he o ce needed o emo e he film om he od, esul ing
in a ough su ace. This may po en ially affec he in eg i y o he
films. Figu e 1b shows he films ab ica ed wi h a 30% PCL solu-
ion. A smoo h su ace and uni o m hickness can be obse ed.
Films made om a 40% PCL solu ion a e shown in Figu e 1c.
The highe concen a ion led o a highe iscosi y in his case,
he e o e hey did no sp ead e enly ac oss he su ace o he
me al od, esul ing in a ough and nonuni o m su ace o he
films.
The 30% PCL o mula ion was chosen o ab ica e films wi h
diffe en hicknesses o coa ings. The physical appea ance o he
films is shown in Figu e 2All he films we e o med well, wi h
p ope hickness and smoo h and uni o m su ace.
Simila me hods ha e been used be o e o ob ain ubula
memb anes/scaffolds. These me hods no mally use elec ospin-
ning o 3D-p in ing on he su ace o a od o a cylind ical s uc-
u e o ob ain ubula objec s.[23]An al e na i e o his is he use
o ho -mel ex usion bu his echnique no mally equi es he
use o la ge amoun s o polyme and he e o e i is no ideal o
he p epa a ion o small p o o ypes.[24]
Op ical cohe ence omog aphy (OCT) is an imaging echnol-
ogy ha e alua es biological issue. Howe e , i can be used
o isualize o he samples including pha maceu ical p oduc s
o medical de ices.[25]In his case, OCT is used o obse e
he c oss-sec ion o films and assembled implan able de ices.
Figu e 2a,d,g,j shows he images o films wi h diffe en laye s
o coa ings, in which i can be seen ha e e y film is uni o m,
and no gap can be obse ed. Diffe en hicknesses can also be
obse ed, as shown in Figu e 3a; he hickness inc eased wi h
he inc ease o laye s o coa ings in a linea way. The hickness
o he memb anes o 4, 5, 6, and 7 laye s was: 120 ±9, 211 ±6,
300.67 ±8, and 412 ±10 μm espec i ely. The coa ing p ocess
was consis en , wi h a significan diffe ence (p<0.05) obse ed in
hese ou films wi h diffe en laye s o coa ings. These esul s in-
dica e ha he me hod p oposed can be easily adap ed o modi y
memb ane hickness and ha he o e all hickness o he mem-
b ane will be simple o p edic as he e is a linea ela ionship
be ween he numbe o laye s and he memb ane hickness. The
hickness o hese memb anes is in line wi h p e iously epo ed
films used as a e-con olling memb anes in implan able de ices
anging be ween 70 and 400 μm.[19a,24,26]
Figu e 1. Physical appea ance o films wi h diffe en concen a ions o PCL. a) 20% PCL in DCM b) 30% PCL in DCM c) 40% PCL in DCM.
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Figu e 2. Physical appea ance and OCT images o c oss-sec ion o 30% PCL films wi h diffe en hicknesses. a–c) 4 coa ings d– ) 5 coa ings g–i) 6
coa ings j–l) 7 coa ings. The scale ba o OCT images is 1 mm.
Figu e 3. Thickness o memb anes wi h diffe en numbe o laye s (a) (means ±s.d., n=5). Po e size dis ibu ion cu es o memb ane samples (b).
Co ela ion be ween o al su ace a ea (TSA) and memb ane hickness (c).
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Table 3. Tex u al p ope ies o he polyme ic memb anes ob ained by MIP.
Sample TSA [m2g−1]TPV[cm
3g−1]
4 coa ings 20.281 0.089
5 coa ings 21.195 0.108
6 coa ings 21.374 0.089
7 coa ings 23.846 0.138
The po osi y o he memb anes was e alua ed using MIP
(Figu e 3b). All he analyzed samples had a simila monomodal
po e size dis ibu ion wi h a peak alue cen e ed a ound 1 μm.
Howe e , he addi ion o mo e laye s in he 7 coa ings mem-
b anes sample p oduced he mos uni o m shape wi h an im-
po an inc ease o he po e size dis ibu ion in ensi y, which in-
dica es a la ge numbe o po es wi h same size o a ound 1 μm.
The e o e, he hickness inc ease o he 7 coa ings memb ane
samples esul ed in a la ge numbe o po es o he same size
(a ound 1 μm) han he es o he memb ane samples. The ob-
ained po e dis ibu ion is in line wi h p e iously epo ed PCL-
based memb anes showing po es anging be ween 1 and 2 μm.
The ou comes shown in Table 3e idenced an inc ease o he
memb ane o al su ace a ea (TSA) associa ed o he gene al in-
c ease o po es popula ion a e inc easing he numbe o coa -
ings. These esul s also confi med he gene al end by which
mos o he memb anes had highe alues o he o al po e ol-
ume (TPV) when he numbe o coa ings was inc eased as can be
seen in Figu e 3c. Finally, he highe po e in olume is di ec ly
co ela ed wi h a highe po osi y pe cen age, as epo ed by S ew-
a e al.
[27]I is impo an o men ion ha his is a mo e consis-
en me hod o p epa ing a e-con olling memb anes o im-
plan able de ices. P e ious s udies epo ed he use o his ype
o memb ane, bu hey we e w apped a ound a d ug-con aining
co e and sealed.[28]This p ocedu e is mo e ime-consuming and
equi es ex ensi e memb ane sealing in he edges o a oid d ug
leakages. This is minimized i memb anes a e p epa ed in a
ubula shape.
Figu e 4shows SEM images o he memb anes wi h diffe en
coa ings. The memb anes exhibi po e sizes anging be ween 2
and 8 μm in diame e . These esul s a e consis en wi h he po e
sizes ob ained using MIP (Figu e 3b). I is impo an o no e ha
o some memb anes, mul iple small po es sligh ly dis o he
po e dis ibu ion. The po e size dis ibu ion is ep esen ed as he
equency o he po es. These small po es cons i u e a small po -
ion o he o al po e a ea. The esul s om MIP indica e ha
hese small po es do no con ibu e o he diffe en ial in usion
(Figu e 3b). Addi ionally, he equency o po es anging be ween
2and8μm is simila ac oss all samples, ega dless o he numbe
o coa ings.
2.3. P epa a ion o RIS Implan able De ices and In Vi o D ug
Release Expe imen s
The mini RIS implan able de ice was assembled om a RIS pel-
le and a PCL ube. The mel ing poin o PCL is be ween 50 and
60 °C,[29]so he sealing p ocess can be easily pe o med using
hea ed plie s. By adjus ing he numbe o pelle s loaded in o he
PCL ube, he d ug loading o his implan able de ice can be ad-
jus ed. Figu e 5ap esen s a comple ed RIS implan able de ice.
The OCT c oss-sec ion image o an implan able de ice is shown
in Figu e 5b. In his case, i shows he RIS pelle was igh filled
in he film. The ou e pa is clea e han he inne pa due o
he pene a ion o he lase .
The in i o elease s udies we e ca ied ou o u he un-
de s and he elease beha io o RIS in implan able de ices. All
g oups we e pe o med un il all he d ug was comple ely eleased
om he implan able de ices o un il he s udy was s opped. Ini-
ially, in i o, elease s udies we e conduc ed wi h implan able
de ices con aining diffe en composi ions o d ug and excipien
unde he same hickness o films. The aim o his was o de-
e mine he influence o d ug composi ion. The fi s s ep was o
s udy he elease o RIS om he uncoa ed pelle s. As p esen ed
in Figu e 6, hese cu es a e all simila and elease all he d ugs
in 20 days. When e alua ing simila i y and diffe ence ac o s, i
he alue o F1is be ween 0 and 15, and he alue o F2is be-
ween 50 and 100, hen he wo elease p ofiles a e conside ed
simila .[30]As lis ed in Table 4, he esul s sugges ha he elease
om R50P50 and R60P40 can be conside ed equi alen . RIS e-
leased om R40P60 and R60P40 canno be conside ed equi alen
acco ding o F1and F2 esul s. Finally, he esul s ob ained o he
compa ison o R40P60 and R50P50 cu es showed some disc ep-
ancies be ween F1and F2 ac o s bu conside ing how close he
calcula ed alues we e o he h eshold limi i can be assumed
ha he cu es a e equi alen . The compa ison o F1and F2 ac-
o s be ween R40P60 in 4 coa ings and R50P50 in 4 coa ings,
R40P60 in 4 coa ings and R60P40 in 4 coa ings, and R50P50 in 4
coa ings and R60P40 in 4 coa ings can also alida e abo e conclu-
sion. Fu he mo e, by compa ing he F1and F2 ac o s be ween
R40P60 and R40P60 in 4 coa ings, R50P50 and R50P50 in 4 coa -
ings, and R60P40 and R60P40 in 4 coa ings, i can be concluded
ha hey we e diffe en in each compa ison, which p o ed he
impac o PCL films on slowing elease a e.
When he pelle s we e coa ed wi h he ubula a e-con olling
memb ane, he RIS elease a e was slowed down significan ly
as p esen ed in Figu e 6. I is impo an o no e ha hese e-
sul s sugges ha he use o PCL-based memb anes can sus ain
he elease o RIS o up o 70 days. The elease du a ion is p o-
po ional o he d ug loading. Lowe d ug loadings esul ed in
a sho e elease du a ion (≈40 days). When compa ing he e-
sul s o he RIS elease om he pelle s wi h he elease om he
coa ed implan s F1and F2 ac o s indica e ha he elease cu es
a e diffe en . The diffe ences be ween he coa ed implan s a e
mo e ob ious and i can be es ablished ha he highe he d ug
loading he slowe is he elease. The compa ison o he cu es
using F1and F2confi ms hese esul s. This may be because PEG
is a hyd ophilic polyme ha could assis in he solubiliza ion
o hyd ophobic d ugs. Simila esul s ha e been obse ed p e-
iously o o he hyd ophobic d ugs such as olanzapine, whe e
PEG inc eased he solubili y o he d ug.[28b]
D ug elease om ese oi sys ems is influenced by a -
ious pa ame e s and ypically ollows a diffusion-con olled
mechanism.[31]Fo he d ug o be eleased, wa e mus pe mea e
he memb ane, pa ially dissol ing he d ug wi hin i . The dis-
sol ed d ug hen diffuses h ough he memb ane and is eleased,
c ea ing a concen a ion g adien be ween he implan co e and
i s ex e nal en i onmen .[31]Also, i is impo an o men ion ha
he concen a ion g adien and, he elease a e, will be p opo -
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Figu e 4. SEM images o he memb anes and po e size dis ibu ion ob ained om SEM images. Scale ba : 100 μm.
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Figu e 5. a) Image o an accomplished RIS implan able de ice. b) Rep esen a i e OCT image o he c oss-sec ion o he implan able de ice wi h an
R60P40 o mula ed pelle in 4 coa ings film. The scale ba o OCT images is 1 mm.
ional o d ug solubili y inside he implan co e.[31]I he con-
cen a ion g adien emains cons an , he sys em exhibi s ze o-
o de elease. To sus ain his g adien , he co e mus con ain a
sufficien quan i y o d ug o main ain a sa u a ed d ug solu ion.
This includes bo h dissol ed d ug and undissol ed d ug ese es.
As d ug molecules a e eleased, he undissol ed d ug eplenishes
he dissol ed po ion, p ese ing sa u a ion condi ions wi hin he
de ice. Howe e , as he d ug load diminishes o e ime, he sys-
em e en ually ails o main ain sa u a ion, causing he elease
a e o slow. This deple ion explains he de ia ion om linea i y
obse ed in Figu e 6du ing he la e s ages o elease.
Ano he in i o elease s udy was pe o med wi h implan able
de ices using di ec ly comp essed pelle s wi h he same o mula-
ion bu coa ed wi h diffe en laye s o film o e alua e he impac
o film hickness. As shown in Figu es 7aand 8a, he elease o
bo h RIS-PEG pelle s and RIS-HP𝛽CD pelle s occu ed apidly,
in 22 and 24 days, espec i ely. They canno be compa ed wi h
RIS pelle s because pu e RIS could no o m a di ec ly com-
p essed pelle on i s own. In Figu e 7., all hese de ices showed
sus ained elease o d ugs, and no bu s elease was obse ed
ini ially. The esul s indica ed ha he elease beha io was
significan ly influenced by he hickness o he films. Wi h an
inc ease in film hickness, he elease a e became slowe , ang-
ing om 70 o 170 days depending on he hickness o he film.
The elease a e co ela es wi h memb ane hickness in a linea
way as shown in Figu e 6d. These implan able de ices exhibi ed
a linea d ug elease a e du ing hei elease ime. Thicke
memb anes will lead o a longe diffusion pa h o he dissol ed
d ug. This leads o slowe elease kine ics as demons a ed
p e iously.[26a,c,32]
Figu e 6. In i o cumula i e elease p ofile o PEG-RIS pelle s. Release
s udies we e ca ied ou in iplica e (n=3) and all esul s we e exp essed
as means ±s.d.
Figu e 8shows he cumula i e elease p ofile o implan able
de ices made om R60C40 pelle s and diffe en laye s o films.
All ou g oups showed as e elease in he fi s 10 days, a e
which he elease a e became slowe , exhibi ing a linea d ug e-
lease a e un il all he d ugs we e eleased om he implan able
de ices. The ime anged om 100 o 180 days depending on he
hickness o he film. The esul s sugges ed ha he use o HP-
𝛽CD can be used o ex end RIS elease. Howe e , as men ioned
ea lie , hese cu es showed a biphasic elease pa e n. The ini-
ial elease a e is as e due o he p esence o HP-𝛽CD in he
pelle . Cyclodex ins and hei de i a i es ha e been ex ensi ely
Table 4. Diffe ence and simila i y ac o s calcula ed o each elease p ofile
o implan able de ices.
Cu e 1 Cu e 2 F1 F2
R40P60 R50P50 16 53
R40P60 R60P40 26 43
R50P50 R60P40 11 62
R40P60 R40P60 in 4 coa ings 142 18
R50P50 R50P50 in 4 coa ings 151 19
R60P40 R60P40 in 4 coa ings 63 20
R40P60 in 4 coa ings R50P50 in 4 coa ings 17 51
R40P60 in 4 coa ings R60P40 in 4 coa ings 26 42
R50P50 in 4 coa ings R60P40 in 4 coa ings 9 60
R60P40 in 4 coa ings R60P40 in 5 coa ings 23 38
R60P40 in 4 coa ings R60P40 in 6 coa ings 54 21
R60P40 in 4 coa ings R60P40 in 7 coa ings 58 20
R60P40 in 5 coa ings R60P40 in 6 coa ings 41 33
R60P40 in 5 coa ings R60P40 in 7 coa ings 47 30
R60P40 in 6 coa ings R60P40 in 7 coa ings 12 67
R60C40 in 4 coa ings R60C40 in 5 coa ings 36 37
R60C40 in 4 coa ings R60C40 in 6 coa ings 48 31
R60C40 in 4 coa ings R60C40 in 7 coa ings 48 31
R60C40 in 5 coa ings R60C40 in 6 coa ings 17 63
R60C40 in 5 coa ings R60C40 in 7 coa ings 19 60
R60C40 in 6 coa ings R60C40 in 7 coa ings 3 90
R60P40 in 4 coa ings R60C40 in 4 coa ings 29 32
R60P40 in 5 coa ings R60C40 in 5 coa ings 42 33
R60P40 in 6 coa ings R60C40 in 6 coa ings 19 60
R60P40 in 7 coa ings R60C40 in 7 coa ings 21 63
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Figu e 7. In i o elease p ofile o R60P40 pelle in diffe en hicknesses o PCL ubes. a) Cumula i e RIS eleased in pe cen age. b) Cumula i e RIS
eleased in millig ams. c) RIS eleased in mg pe day. Release s udies we e ca ied ou in iplica e (n=3) and all esul s we e exp essed as means ±s.d.
d) Co ela ion be ween memb ane hickness and RIS elease a e.
Figu e 8. In i o elease p ofile o R60C40 pelle in diffe en hicknesses o PCL ubes. a) Cumula i e RIS eleased in pe cen age. b) Cumula i e RIS
eleased in millig ams. c) RIS eleased in mg pe day. Release s udies we e ca ied ou in iplica e (n=3) and all esul s we e exp essed as means ±s.d.
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