Jou nal o D ug Deli e y Science and Technology 99 (2024) 105973
A ailable online 15 July 2024
1773-2247/© 2024 The Au ho s. Published by Else ie B.V. This is an open access a icle unde he CC BY license (h p://c ea i ecommons.o g/licenses/by/4.0/).
Rese oi - ype in anasal implan s o sus ained elease o ispe idone: A
po en ial al e na i e o long- e m ea men o schizoph enia
Emilia U omo
a
, Linlin Li
a
, Jiaqi Gao
a
, Qoni a Ku nia Anjani
a
, Camila J. Picco
a
,
Na alia Mo eno-Cas ellanos
b
, Ryan F. Donnelly
a
, Juan Domínguez-Robles
a,c,**
,
Eneko La a˜
ne a
a,*
a
School o Pha macy, Queen’s Uni e si y Bel as , 97 Lisbu n Road, Bel as , BT9 7BL, UK
b
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
c
Depa men o Pha macy and Pha maceu ical Technology, Facul y o Pha macy, Uni e si y o Se ille, 41012, Se ille, Spain
ARTICLE INFO
Keywo ds:
In anasal
Long-ac ing d ug deli e y
Rese oi - ype implan
Rispe idone
Memb ane
ABSTRACT
To o e come he challenges o he blood-b ain ba ie o d ug deli e y o he cen al ne ous sys em (CNS),
in anasal implan s we e de eloped o imp o e he managemen o CNS condi ions, such as schizoph enia. In he
p esen wo k, we de eloped and cha ac e ised a d ug-con aining implan consis ing o wo pa s: a co e laye
made om ispe idone (RIS) and wa e -soluble polyme s, including poly( inylpy olidone) (PVP) and poly
(e hylene glycol) (PEG), and a coa ing laye made o poly(cap olac one) (PCL) memb ane. The ob ained im-
plan s, whe e he co e laye con ained 75 % w/w ispe idone, we e cha ac e ised using se e al echniques:
scanning elec on mic oscopy (SEM), he mog a ime ic analysis (TGA), di e en ial scanning calo ime y (DSC),
and a enua ed o al e lec ance-Fou ie ans o m in a ed (ATR-FTIR). Mo eo e , he in i o elease p o ile o
RIS was s udied, showing ha he PCL memb ane could ex end he elease o RIS om 2 days up o 100 days. The
in i o elease p o ile o he PCL-coa ed implan exhibi ed a linea elease o e he i s 10 days, ollowed by a
slowe elease a e ha eached ano he linea phase up o 40 days. Subsequen ly, he d ug elease a es p o-
g essi ely slowed down. Finally, he esul s o in i o biocompa ibili y s udies indica ed ha he in anasal
implan s we e biocompa ible and non-cy o oxic. These indings sugges ha he implan s p epa ed in his wo k
ha e he po en ial o p o ide long-ac ing d ug deli e y o a ge ing he b ain.
1. In oduc ion
The p esence o he blood-b ain ba ie limi s he deli e y o d ugs
in o he cen al ne ous sys em (CNS) [1,2]. Acco dingly, he de elop-
men o sys ems capable o bypassing his ba ie o enhance d ug
adminis a ion in o he b ain has a ac ed a en ion o e he pas de-
cades [3,4]. A po en ial al e na i e ou e o adminis a ion o maximise
d ug concen a ions in he CNS is he in anasal ou e [5–10]. Se e al
s udies ha e desc ibed he e icacy o his ou e in enhancing b ain d ug
le els.
I is impo an o no e ha many condi ions a ec ing he CNS a e
ch onic and equi e egula pha macological ea men . No mally, hese
d ugs a e adminis e ed ia he o al ou e. Despi e being he p e e ed
ou e o d ug adminis a ion, i p esen s challenges o he managemen
o ch onic condi ions, as he pa ien needs o adhe e o he ea men
[11,12]. A po en ial al e na i e o sol e his issue is long-ac ing d ug
deli e y sys ems [13–17]. These sys ems a e ypically injec ed o
implan ed in o he pa ien , p o iding sus ained d ug dosage a e a
single adminis a ion [13–18]. Long-ac ing d ug deli e y sys ems ha e
been p epa ed in a wide ange o shapes and ma e ials including solid
subcu aneous implan s [14,19,20], injec able suspensions [21,22] o in
si u o ming implan s/gels [23–26]. Thei applica ion is in asi e, unlike
he o al ou e, bu hei bene i in e ms o adhe ence o ea men can
ou weigh his limi a ion [17,27].
A no el s a egy ha combines he ad an ages o long-ac ing d ug
deli e y sys ems and he in anasal ou e o adminis a ion is d ug-
elu ing in anasal implan s [28,29]. These sys ems can be implan ed
in he pa ien ’s nasal ca i y o p o ide sus ained d ug elease. I is
* Co esponding au ho .
** Co esponding au ho . School o Pha macy, Queen’s Uni e si y Bel as , 97 Lisbu n Road, Bel as , BT9 7BL, UK.
E-mail add esses: [email p o ec ed] (J. Domínguez-Robles), [email p o ec ed] (E. La a˜
ne a).
Con en s lis s a ailable a ScienceDi ec
Jou nal o D ug Deli e y Science and Technology
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Recei ed 11 June 2024; Recei ed in e ised o m 8 July 2024; Accep ed 11 July 2024
Jou nal o D ug Deli e y Science and Technology 99 (2024) 105973
2
impo an o men ion ha d ug elu ing in anasal implan s ha e been
desc ibed ex ensi ely o ea men o nasal polyps [30–32]. Howe e ,
hey a e designed o localised d ug deli e y. In anasal implan s aimed
o b ain d ug deli e y a e a no el app oach. Such de ices can be used o
imp o e he managemen o condi ions a ec ing he CNS, such as
schizoph enia.
Schizoph enia is a ch onic condi ion ha se e ely a ec s pa ien s,
dis o ing pe cep ion and hei way o hinking [33]. The ea men o
his condi ion elies hea ily on pha macological in e en ions. As
men ioned ea lie , adhe ence o ea men can be challenging in ch onic
condi ions, and schizoph enia is no excep ion [34–36]. I has been e-
po ed ha up o 75 % o pa ien s su e ing om his condi ion expe-
ience ea men adhe ence issues [34]. This can lead o elapse,
dec easing he quali y o li e o pa ien s while inc easing
heal hca e-associa ed cos s [36–38]. Addi ionally, d ugs used o ea
schizoph enia, such as ispe idone (RIS) [39], ha e side e ec s [40–43]
when a e adminis e ed o ally, a ec ing he quali y o li e o pa ien s and
po en ially con ibu ing o poo adhe ence [44,45]. D ug-elu ing in a-
nasal implan s can be used o schizoph enia ea men as hey p o ide
sus ained d ug elease, maximising he amoun o d ug adminis e ed
in o he b ain while educing sys emic exposu e and he eby educing
side e ec s.
This wo k will desc ibe he de elopmen o ese oi - ype implan -
able in anasal implan s o schizoph enia ea men . Fo his pu pose, a
d ug-con aining implan was p epa ed using wa e -soluble polyme s
and RIS. I was subsequen ly encapsula ed inside a biocompa ible a e-
con olling memb ane made o poly(cap olac one) (PCL). The im-
plan s we e ex ensi ely cha ac e ised, employing a comp ehensi e a ay
o physicochemical echniques. Mo eo e , in i o RIS elease and
biocompa ibili y s udies we e pe o med.
2. Ma e ials and me hods
2.1. Ma e ials
RIS was pu chased om Enke Pha ma-Tech Co., l d (Cangzhou,
China). Poly(e hylene glycol) (PEG) (Mw =600 Da) was pu chased om
Tokyo Chemical Indus ies (Tokyo, Japan). Poly( inyl py olidone)
(PVP) (360 kDa) was pu chased o Sigma-Ald ich (S einheim, Ge -
many). High (CAPA ®6506; Mw =50 kDa) and low (CAPA®2054; Mw
=550 Da) molecula weigh PCL we e kindly dona ed by Inge i y
(No h Cha les on, Sou h Ca olina, U.S.A). Phospha e saline bu e ed
saline (PBS) (pH 7.4) able s we e ob ained om VWR In e na ional
(Leu en, Belgium. Dichlo ome hane (DCM), ace oni ile and me hanol
we e pu chased om Sigma-Ald ich (Do se , UK)
2.2. P epa a ion o ese oi ype implan able de ices
The ese oi - ype implan s consis ed o wo pa s: he co e implan s
p epa ed using hyd ophilic polyme s (PVP and PEG), and he coa ing
laye made o PCL ilm. The p epa a ion o his ype o implan is
illus a ed in Fig. 1A. The co e implan s con aining 75 % w/w o RIS
we e ab ica ed using a sol en cas ing me hod, u ilising PVP (15 % w/
w) and PEG (10 % w/w) as he main polyme s. Wa e was added in a 1:1
a io o he solid con en . The d ug and polyme s we e mixed using a
SpeedMixe ™DAC 150.1 FVZ-K (Hauschild &Co. KG, Hamm, Ge -
many) a 3000 pm o 3 min. The mix u e was cas using a sy inge
inside a silicone mould p epa ed as desc ibed p e iously [28]. Subse-
quen ly he mould con aining he liquid o mula ion was cen i uged a
3500 pm o 30 min o sp ead he o mula ion h ough he moulds. The
implan s we e placed a 37 ◦C o 24 h o d y.
The coa ing laye o PCL ilm was p epa ed using a combina ion o
Fig. 1. Diag ams showing he p o ocols ollowed o : co e implan p epa a ion (A) and ese oi ype assembly (B). Diag am showing he se up used o pe mea ion
expe imen s (C).
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Jou nal o D ug Deli e y Science and Technology 99 (2024) 105973
3
PCL 6506 and PCL 2504 in a 1:1 a io. This a io was selec ed based on
p e ious expe imen s [46]. This mix u e o PCL was subsequen ly dis-
sol ed in DCM o ob ain a concen a ion o 20 % w/w. The PCL solu ion
was hen cas in a Pe i dish and le a oom empe a u e o allow DCM
e apo a ion. Subsequen ly, he coa ing laye was cu based on he shape
o he implan . The p ocedu e used o p epa e he ese oi - ype im-
plan s can be seen in Fig. 1B. The co e implan was placed be ween wo
coa ing laye s, and a hea ed plie was used o seal he implan .
2.3. RIS loaded co e implan cha ac e isa ion
A Hi achi TM3030 able op scanning elec on mic oscope (SEM)
(Hi achi, Tokyo, Japan) was u ilized o examine he su ace mo phology
o RIS-loaded implan s.
To assess in e ac ions be ween RIS and he polyme s, Fou ie
ans o m in a ed (FTIR), di e en ial scanning calo ime y (DSC) and
he mog a ime ic analysis (TGA) and we e conduc ed. Fo DSC, sam-
ples weighing be ween 5 and 10 mg we e hea ed in sealed aluminium
pans om 25 o 200 ◦C a a a e o 10 ◦C/min unde a ni ogen a mo-
sphe e using a DSC Q20 (TA Ins umen s, New Cas le, USA). Fo TGA,
small implan pieces o simila weigh we e hea ed o 500 ◦C a a a e o
10 ◦C/min unde ni ogen low using a TGA Q500 (TA Ins umen s, New
Cas le, USA). Fo DSC and TGA da a analysis was pe o med wi h TA
Uni e sal Analysis so wa e (TA Ins umen s, New Cas le, DE, USA). On
he o he hand, FTIR analysis was pe o med using an Accu ac FT/IR-
4100 se ies spec ome e (Jasco, Essex, UK) equipped wi h a MIRa-
cle™diamond a enua ed o al e lec ion (ATR) accesso y was used. IR
spec a we e eco ded be ween 600 and 4000 cm
−1
, as an a e age o 32
scans and 4.0 cm
−1
o esolu ion.
The RIS con en in he implan s was de e mined by dissol ing he
implan s and measu ing he d ug amoun in he solu ion as desc ibed
p e iously [28]. To quan i y he amoun o d ug in solu ion
High-pe o mance liquid ch oma og aphy (HPLC) was used. The HPLC
condi ions a e desc ibed in he ollowing sec ion.
2.4. HPLC me hod o RIS quan i ica ion
RIS quan i ica ion was conduc ed using an HPLC sys em (Agilen
Technologies, S ockpo , UK). The column used was a Phenomenex®
Sphe eClone™C18 ODS column (leng h: 150 mm leng h; ID: 4.60;
Pa icle size: 5
μ
m). The mobile phase consis ed o an aqueous phase and
an o ganic phase in a a io o 15:85 % / . The aqueous phase con ained
sodium dihyd ogen phospha e bu e (10 mM) and 1 % / o ie hyl-
amine (TEA). The pH o he aqueous phase was adjus ed o 7.2 using
o hophospho ic acid. The o ganic phase was a mix u e o me hanol and
ace oni ile in a 75:25 % / a io.
The injec ion olume was se a 20
μ
L wi h a low a e o 1.2 mL/min,
and de ec ion was ca ied ou using a UV de ec o se a 235 nm. All he
HPLC expe imen s we e ca ied ou a oom empe a u e. Ch oma o-
g am analysis was conduc ed using Agilen ChemS a ion®So wa e
B.02.01. The me hod was p e iously alida ed acco ding o ICH
guidelines [28].
2.5. In i o RIS elease
The elease a e o RIS om he implan s was assessed by quan i ying
he d ug amoun eleased a speci ied ime poin s. Fo his pu pose,
ese oi implan s and he co e sec ion o he implan s wi hou mem-
b ane we e es ed. Each implan was placed in a lask illed wi h 250 mL
o PBS (pH 6.5). Subsequen ly, he lasks we e in oduced in a shaking
incuba o a 37 ◦C, mimicking in anasal condi ions [47], and agi a ed
a 40 pm. To p epa e he elease media he pH o a PBS (pH 7.4) so-
lu ion was adjus ed wi h phospho ic acid (85 %) o achie e he equi ed
pH alue o 6.5. The elease expe imen s we e pe o med unde sink
condi ions, wi h RIS solubili y in PBS (pH 6.5) being 1.24 ±0.06
mg/mL. Fo he expe imen o coa ed implan s, a each ime poin , a 1
mL aliquo o he elease medium was sampled and eplaced wi h an
equal olume o esh PBS (pH 6.5) o main ain sink condi ions. On he
o he hand, he elease om he implan s wi hou memb ane, he
elease was ca ied ou o e 48 h wi hou eplacing he elease media as
he implan s we e soluble and could no be e ie ed om he media
a e hyd a ion. Mo eo e , o main ain sink condi ions, only a agmen
o he implan was used in his case. The collec ed samples we e quan-
i ied using he HPLC me hod desc ibed p e iously (sec ion 2.4). I
necessa y, samples we e dilu ed o ensu e he concen a ion ell wi hin
he ange o he linea calib a ion cu e.
2.6. RIS pe mea ion expe imen
In i o pe mea ion s udies we e conduc ed o e alua e he elease
and di usion o RIS om he implan s, simula ing d ug pe mea ion om
he nasal ca i y o he b ain as depic ed in Fig. 1C. The expe imen al
se up u ilized side-by-side ho izon al di usion cells, each consis ing o
dono and ecep o compa men s wi h wa e jacke s o empe a u e
con ol. A cellulose memb ane (Spec um™Spec a/Po ™2 RC Dialysis
Cellulose Memb ane Tubing, 12–14 kDa MWCO, Fishe Scien i ic,
Van aa, Finland), p e-soaked in PBS (pH 6.5) o 30 min, was secu ed
be ween he compa men s o p e en leakage and e apo a ion.
Bo h compa men s we e illed wi h an equal olume o PBS (pH
6.5), 3 mL, and main ained a 37 ◦C unde con inuous s i ing a 600
pm. A speci ied in e als, he en i e solu ion om he ecep o
compa men was collec ed and eplaced wi h esh PBS (pH 6.5) o
a oid sa u a ion. The collec ed samples we e hen analysed wi h he
alida ed HPLC me hod desc ibed ea lie . Dilu ions wi h PBS (pH 6.5)
we e made when necessa y o ensu e sample concen a ions ell wi hin
he calib a ion cu e ange. The expe imen las ed o 7 days, wi h
samples collec ed e e y 24 h.
2.7. In i o cy o oxici y s udies
In his s udy, human de mal ib oblas s (HDF, ATCC PCS-201-010)
we e employed as model cells. HDF we e cul u ed in Dulbecco’s Modi-
ied Eagle Medium (DMEM). This medium was supplemen ed wi h 10 %
e al bo ine se um, penicillin-s ep omycin (10,000 uni s/10 mg/mL),
and 200 mM L-glu amine. The cells we e main ained a 37 ◦C in a 5 %
CO
2
a mosphe e. Subcul u ing was done when he cells eached 80–90
% con luency. The es samples we e he a e con olling memb anes
p epa ed using high and low molecula weigh PCL. Films we e cu in o
discs (diame e : 13 mm; hickness: 0.1 mm) be o e he cy o oxici y
s udies. Samples we e s e ilised h ough 30 min o UV-C i adia ion.
Cells we e hen seeded on op o he polyme ic samples a a densi y o 2
×10
4
cells/cm
2
using 12-well pla es. Subsequen ly, samples we e
incuba ed o 7 days. Pos incuba ion, he samples we e subjec ed o
a ious assays including cell iabili y, me abolic ac i i y, lac a e dehy-
d ogenase (LDH) elease, and cell p oli e a ion es s.
The cell iabili y es was conduc ed using a con en ional MTT assay,
adap ed om a p e ious s udy [48]. In b ie , he cell-seeded samples
we e insed using PBS o emo e esidual DMEM. Subsequen ly, MTT
solu ion in DMEM was added o each well o a 96-well pla e ollowed by
an incuba ion s ep o 12 h a 37 ◦C. The incuba ion was ca ied ou in
p esence o 5 % CO
2
o allow o mazan c ys al o ma ion. The medium
was subsequen ly emo ed, and he samples we e washed using
dime hyl sul oxide (DMSO). The o mazan c ys als we e dissol ed in he
DMSO. Finally, he abso bance o his solu ion was measu ed a 580 nm
using a Syne gy H1 mic opla e eade (Agilen Technologies, San a
Cla a, USA). Un ea ed HDF cells se ed as he nega i e con ol, while 1
% T i on X-100 was used as he posi i e con ol.
The ela i e me abolic ac i i y o he cells on he bioma e ials was
assessed using an Alama Blue assay. To s a , he cell-seeded samples
we e washed using PBS o elimina e emaining es s o DMEM. Then, 15
μ
L o Alama Blue dye con aining 100
μ
L o phenol ed- ee DMEM was
added o each well o a 96-well pla e. Then, he pla es we e incuba ed a
E. U omo e al.
Jou nal o D ug Deli e y Science and Technology 99 (2024) 105973
4
37 ◦C wi h 5 % CO
2
o 4 h. Fluo escence was measu ed using a pla e
eade wi h exci a ion a 550 nm and emission a 590 nm. HDF cells
seeded wi hou es ma e ials se ed as he con ol.
The LDH assay was employed o quan i y he ex en o HDF cell
memb ane up u e. Samples we e washed wi h PBS and he cells we e
de ached om he samples. Then, he de ached cells we e e-suspended
in DMEM. A 50
μ
L aliquo o cell suspension was ea ed wi h 50
μ
L o
PBS con aining a 2 % ( / ) o T i on X-100 o 30 min a 37 ◦C.
Following his, 100
μ
L o he lysed cell solu ion was aken om each well
and hen combined wi h 100
μ
L o LDH subs a e in a 96-well pla e.
Finally, he luo escence o he samples was measu ed a 630 nm using
an exci a ion wa eleng h o 490 nm.
Cell p oli e a ion was assessed using a DNA con en assay ki . The
DNA con en in cells a ached o he PCL-based ilms was de e mined
using Quan -iT™PicoG een®dsDNA Reagen Ki ollowing he in-
s uc ions p o ided by he manu ac u e . In b ie , samples we e insed
h ee imes wi h PBS and hen subme ged in 1 mL o lysis bu e ha
con ained 10 mM T is (pH 8), 1 mM EDTA, and 0.2 % ( / ) o T i on X-
100. DNA was eleased by o exing he samples o 10 s e e y 5 min
o e a 30-min pe iod, while keeping hem on ice. A e hawing on ice
and homogenizing o 10–15 min, he samples we e combined wi h 100
μ
L o he DNA-binding luo escen dye solu ion. Subsequen ly, hey we e
incuba ed o 30 min a 37 ◦C wi h 5 % CO
2
. Finally, luo escence in-
ensi y o hese solu ions was measu ed a 520 nm using an exci a ion
wa eleng h o 480.
All he esul s ob ained o he cy o oxici y s udies we e compa ed
using an unpai ed - es . Values o p lowe han 0.05 indica ed a s a-
is ically signi ican di e ence be ween es ed g oups.
3. Resul s and discussion
Implan s we e p epa ed using a “ lowe -like”design so hey can be
olded as showed in Fig. 2A. Once hey a e olded, hey can be inse ed
h ough an endoscope and placed inside he nasal ca i y. The di-
mensions o he implan ha e been adap ed om a simila p oduc
designed o localised deli e y o co icos e oids o p e en nasal polyp
ecu ence a e sinus su ge y [49].
In anasal implan s we e p epa ed using a sol en cas ing me hod o
c ea e he co e sec ion o he implan con aining high RIS con en (75 %
w/w). Fig. 2B shows an image o he co e sec ion o he implan . The
co e sec ion o he implan is wa e -soluble; he e o e, o slow down
d ug elease om in anasal implan s, a a e-con olling memb ane
coa ing should be added. Fo his wo k, a PCL-based memb ane was
selec ed, combining wo di e en molecula weigh PCLs as epo ed
ea lie [46]. This ype o memb ane p esen s a de ined po osi y and po e
diame e o 20 % and 1–2
μ
m, espec i ely. Due o his s uc u e, hese
memb anes ha e been used success ully o sus ain he deli e y o hy-
d ophilic compounds o up o 200 days [46]. Acco dingly, soluble RIS
in anasal implan s we e coa ed wi h he a o emen ioned memb ane, as
can be seen in Fig. 2C.
P io o e alua ing he pe o mance o he in anasal implan s, he
d ug-con aining co e implan was cha ac e ised. SEM mic og aphs
showed ha he e we e no ob ious d ug pa icles o c ys als on he
su ace o he implan s, sugges ing ha he d ug is well mixed wi h he
PVP/PEG ma ix. Howe e , i is impo an o no e ha RIS does no ha e
high wa e solubili y, and acco dingly, he esul ing slu y used o
p epa e he implan s will con ain pu e RIS pa icles. This is e iden om
he colou o he implan s, as hey displayed a whi e colou due o he
d ug being in suspension wi hin he s uc u e. Ne e heless, due o he
high-speed mixing p ocess, he d ug is expec ed o be dis ibu ed
h oughou he implan . Also, he p esence o PEG will con ibu e o
inc ease d ug solubili y wi hin he polyme ma ix as desc ibed p e i-
ously [20,50]. To con i m homogenei y o d ug wi hin he implan he
d ug con en in he implan was e alua ed. I was ound ha he d ug
con en was 74.3 ±0.9 %, aligning wi h he ini ial 75 % d ug loading in
he o mula ion used o cas he implan . The amoun o RIS loaded pe
implan was measu ed o be 240 ±7.5 mg.
The use o d ug/polyme slu ies o he p epa a ion o solid objec s
ha e been epo ed be o e, especially o 3D-p in ing applica ions whe e
he iscosi y o he slu y allowed o add laye s o ma e ial o o m a 3D
objec . This app oach has been used wi h aqueous based slu ies o
p epa e o al dosage o ms and pa en e al de ices [51–54]. On he o he
hand, slu ies p epa ed using o ganic sol en s ha e been desc ibed oo
o he p epa a ion o o al dosage o ms o subcu aneous implan s [20,
55]. In hese cases, he d ug was homogeneously dispe sed wi hin he
ma ix, bu d ug c ys als we e ound in he o mula ion.
Fig. 2. Co e implan dimensions diag am (A). Images o RIS-loaded co e implan (B) and coa ed implan (C). SEM mic og aphs o RIS-loaded co e implan (D).
E. U omo e al.
Jou nal o D ug Deli e y Science and Technology 99 (2024) 105973
5
DSC esul s con i med ha he d ug loaded in o he implan
emained in i s c ys alline o m, as he mel ing poin o RIS can be
clea ly seen a a ound 170 ◦C (Fig. 3A). This is he only meaning ul peak,
as PVP and PEG did no show any ob ious ansi ion apa om he
dehyd a ion peak o PVP a a ound 100 ◦C. In e es ingly, he peak
ob ained in he implan DSC was b oade and less in ense han ha o
he pu e d ug. Addi ionally, he mel ing poin was sligh ly lowe . These
esul s indica e ha he c ys allini y o he d ug was a ec ed when
combined wi h PVP and PEG. A ac ion o he ini ial RIS loading will be
soluble in wa e and will in e ac wi h PVP and PEG in solu ion. PVP is a
well-known polyme ha o ms in e ac ions wi h hyd ophilic and hy-
d ophobic d ugs [56], so i is no su p ising ha he d ug shows some
in e ac ions wi h he polyme s. These esul s a e simila o he ones
ob ained p e iously when combining RIS wi h biodeg adable polyme s,
PCL and poly(lac ic-co-glycolic acid) (PLGA) [28]. Also equi alen
beha iou was ound o o he d ugs, such as pa ace amol o olanzapine,
loaded in polyme ic o mula ions p epa ed using aqueous slu ies [51,
54]. The DSC esul s can be con i med by TGA (Fig. 3B). Pu e RIS s a ed
o deg ade a a ound 240 ◦C. Howe e , he d ug loaded in o he co e
implan s s a ed he deg ada ion p ocess a sligh ly highe empe a u es
o a ound 250 ◦C. In e es ingly, he deg ada ion o pu e PEG s a s a
lowe empe a u es han he co e implan . Acco dingly, he combina ion
o he d ug wi h hese wo polyme s sugges s he onse o non-co alen
in e ac ions, leading o he s abilisa ion o hese molecules.
FTIR was used o cha ac e ise he co e implan . Fig. 3C shows he
FTIR spec a o RIS. The cha ac e is ic peaks o he molecule can be
seen clea ly: bands ound a ound 3060 and 1640 cm
−1
can be a ibu ed
o he s e ching o he a oma ic C–H bonds and he ca bonyl g oup o
he δ-lac am ing, espec i ely. Addi ionally, he FTIR o he pu e d ug
shows a oma ic C–C s e ching a a ound 1600 and 1530 cm
−1
. Weake
peaks a ound 1400 cm
−1
, assigned o C–N and C–O angula de-
o ma ions o he oxazole ing, we e also de ec ed. C–N s e ching bands
o he oxazole ing we e obse ed a ound 1350 cm
−1
, while he
s e ching o he e ia y amine o he pipe idine ing was obse ed a
a ound 1190 cm
−1
. Finally, he a yl luo ide g oup o he RIS molecule
can be obse ed a a ound 1130 cm
−1
.
On he o he hand, he FTIR spec a o PVP show cha ac e is ic peaks
a a ound 3450 cm
−1
o O–H s e ching, a ound 2950 cm
−1
o C–H
s e ching, and a ound 1650 cm
−1
o C
–
–
O s e ching. Also, he cha -
ac e is ic band o he C
–
–
N o he py idine ing can be obse ed a
a ound 1500 cm
−1
. The spec a o pu e PEG show bands a a ound 2890,
1350, and 1100 cm
−1
a ibu ed o C–H s e ching, C–H bending, and
C–O s e ching ib a ions, espec i ely.
The FTIR spec a o he co e implan show he cha ac e is ic peaks o
RIS, PVP, and PEG. Du ing he o mula ion, no chemical bonds we e
o med; he e o e, he e we e no new peaks in he FTIR spec a o he
o mula ions. The mal analysis esul s sugges ed some in e ac ions be-
ween RIS and he polyme s. This can be obse ed in Fig. 3D, which
p esen s a magni ied e sion o he FTIR spec a be ween 1700 and
1500 cm
−1
. In his igu e, i can be seen ha he RIS ca bonyl peak
o e laps wi h he ca bonyl peak o PVP, bu he e is a sub le peak
displacemen o highe wa enumbe s. Simila beha iou can be
obse ed o he a oma ic C–H s e ching band a a ound 1530 cm
−1
.
This beha iou has been epo ed o RIS complexes wi h cyclodex ins
[57–59]. Also, he FTIR o he co e implan p esen ed a double peak a
a ound 1100 cm
−1
ha would co espond o he o e lapping o cha -
ac e is ics peaks o RIS and he C–O s e ching ib a ion o he PEG.
A e cha ac e ising he co e implan , he nex s ep was o e alua e
RIS elease om he esul ing implan s. Fig. 4A shows ha he elease
om he PVA/PEG/RIS co e implan ma e ial is as , wi h mo e han 50
% o he d ug ca go eleased a e 2 h and he elease comple ed a e 24
h. As an icipa ed, hese implan s equi e a coa ing o slow down d ug
elease o p o ide sus ained d ug elease o e p olonged pe iods.
The e o e, coa ed implan s we e es ed. Coa ed implan s showed slowe
d ug elease kine ics, p o iding RIS elease o up o 100 days (Fig. 4B).
These implan s did no show an ini ial d ug bu s elease, as he PCL-
Fig. 3. DSC (A), TGA (B) and FTIR (C) cu es o pu e RIS, PVP, PEG and RIS-con aining co e implan . FTIR o pu e RIS, PVP and co e implan be ween 1700 and
1500 cm
−1
(D).
E. U omo e al.
Jou nal o D ug Deli e y Science and Technology 99 (2024) 105973
6
based memb ane con ols d ug elease. PCL and poly(lac ic acid)-based
memb anes ha e been used be o e o sus ain d ug elease [46,60,61].
Semipe meable memb anes a e capable o p o iding ze o-o de elease
[62], as he d ug concen a ion g adien depends on d ug solubili y
wi hin he implan . I a supe sa u a ed sys em is achie ed, he sys em
can p o ide ze o-o de elease as luid pe mea es inside he memb ane,
subsequen ly dissol ing he d ug in he luid o pe mea e h ough he
memb ane. I he implan con ains a supe sa u a ed d ug suspension, a
cons an d ug elease can be achie ed.
In his case, a linea elease can be obse ed o e he i s 10 days,
while subsequen ly, he elease a es slow down o each ano he linea
elease phase up un il 40 days. In he ollowing days, he d ug elease
a es slow down p og essi ely. This can be explained by he p esence o
PVP and PEG in he implan , which con ibu e o inc easing RIS solu-
bili y du ing he ini ial phases o he elease [28]. Ini ially, RIS elease
a es a e highe as he solubili y o he d ug inside he implan is highe
when PVP/PEG a e p esen . These wo polyme s ha e high wa e solu-
bili y and, unlike RIS, will dissol e as e and he e o e will be eleased
du ing he i s days o he expe imen . A e he polyme s a e eleased,
he elease is p opo ional o RIS solubili y on i s own inside he de ice.
The inal change in he elease a e is mainly due o he deple ion o RIS
inside he implan . As men ioned ea lie , i he concen a ion o d ug
dissol ed inside he implan dec eases, his will lead o a dec ease in he
elease a es. Fig. 4C shows he daily elease a e, highligh ing he h ee
main s ages o he elease om he implan s.
I is also impo an o men ion ha he dose ob ained o a single
implan is he apeu ically ele an , as he equi ed RIS dose o mos
pa ien s anges be ween 1 and 2 mg pe day o ally. Conside ing he o al
bioa ailabili y o he d ug, a ound 70 % [63], he equi ed dose o RIS
anges be ween 700
μ
g and 1.4 mg. The a ge si e o ac ion o RIS is he
CNS and conside ing ha in anasal d ug deli e y shows po en ial o
achie e highe d ug concen a ions wi hin he b ain while educing
sys emic d ug exposu e, he equi ed doses could be e en lowe . This
sugges s ha implan dimensions can be educed o load less d ug inside.
Howe e , he p esen ed esul s indica e ha he p oposed in anasal
implan s can p o ide sus ained d ug elease o he apeu ically ele an
doses in i o.
We ha e p e iously epo ed he use o in anasal implan s o RIS
deli e y h ough monoli hic implan s [28,29]. These implan s we e
p epa ed using biodeg adable polyme s, including PCL and PLGA. All
hese implan s showed some ini ial bu s elease due o he di usion o
he d ug loaded on he su ace. Addi ionally, hese sys ems p o ided
as e d ug elease, showing elease p o iles o up o 28 days a e in i o
es ing. PLGA showed longe elease p o iles, bu a e 28 days, he
elease a e was ex emely slow. Acco dingly, coa ed implan s manu-
ac u ed in his wo k p esen ad an ages o e he p e iously men ioned
monoli hic ype implan s.
In anasal implan s should elease he d ug ca go in o he nasal
mucosa, and subsequen ly, he d ug should pe mea e h ough he issue
o each he b ain. To simula e he pe mea ion o RIS h ough nasal
mucosa o e se e al days, a cellulose memb ane was used. The main
eason o choosing his model is ha i is no possible o pe o m he
expe imen o e p olonged pe iods using biological issue, as i will
decompose and deg ade, limi ing he esul s ob ained. Addi ionally, he
use o cellulose memb anes o mimic nasal mucosa has been p e iously
desc ibed by o he au ho s. Ka asulu e al. compa ed he pe meabili y o
indome hacin ac oss di e en syn he ic memb anes (including cellulose
and nylon) and compa ed he esul s wi h d ug pe mea ion ac oss
excised sheep nasal mucosa [64]. The esul s sugges ed ha cellulose
memb anes p o ided he closes pe mea ion p o iles o hose ob ained
o he excised issue. In a di e en s udy, Ba os e al. showed simila
esul s [65]. Acco dingly, cellulose memb anes we e used o e alua e
RIS pe mea ion in a side-by-side F anz cell se up. The esul s ob ained
can be seen in Fig. 4D. The pe mea ion p o ile ollowed a linea pa e n
as i is p opo ional o he d ug concen a ion in he dono compa men .
The pe mea ion is p opo ional o he elease p o ile, as seen in Fig. 4D.
Howe e , pe mea ion ac oss he simula ed nasal mucosa is slowe . The
main eason o his is ha he olume o luid p esen in he F anz cell
se up is smalle , and he e o e, he solu ion could become sa u a ed
mo e quickly. This will main ain a cons an d ug adminis a ion. Addi-
ionally, his sugges s ha he elease du a ion migh be e en slowe in a
eal scena io, as he amoun o luid p esen in he nasal mucosa will be
limi ed. Fo in i o s udies o ensu e ha enough luid pe mea es inside
he implan o acili a e RIS dissolu ion and elease, implan s migh need
o be placed in a ial wi h luid p io o he implan a ion p ocess. In his
case, luid will pe mea e inside and s a he elease p ocess. The e o e,
Fig. 4. RIS elease p o iles om uncoa ed RIS-loaded PVP/PEG ma e ials (A) and coa ed implan s (B). RIS daily elease a e as a unc ion o ime (C). RIS
pe mea ion/ elease p o iles o e a pe iod o 7 days (D). (means +S.D., n ≥3).
E. U omo e al.
Jou nal o D ug Deli e y Science and Technology 99 (2024) 105973
7
once he implan is applied, i will al eady con ain luid, ensu ing ha i
will s a wo king immedia ely, a oiding lag pe iods. This is no a new
s a egy as i has been desc ibed be o e o o he ese oi - ype
implan able de ices [66]. These esul s align wi h he esul s ob ained
p e iously o he pe mea ion o RIS eleased om monoli hic
implan able de ices [28].
A e e alua ing he pe o mance o he esul ing implan s, he inal
s ep was o assess he biocompa ibili y o he PCL-based memb anes.
PVA and PVP a e FDA-app o ed polyme s and hey ha e been ex en-
si ely used o in anasal o mula ions [67–70], and acco dingly, he
es s ocused on he PCL-based memb ane. I is well known ha PCL is a
biocompa ible and biodeg adable ma e ial [71], bu a sol en cas ing
me hod using DCM is equi ed o p epa e hese memb anes. The e o e, a
cy o oxici y es was de eloped o asce ain he cy ocompa ibili y o he
esul ing a e-con olling memb anes. Fo his pu pose, cell iabili y/-
p oli e a ion, me abolic ac i i y, and LDH elease we e e alua ed
(Fig. 5).
The esul s ob ained o he me abolic ac i i y and cell iabili y es s
we e simila . I can be seen ha he cells ea ed wi h he PCL-based
memb ane showed a sligh educ ion in cell iabili y o a ound 25 %
(p <0.0001). The ob ained alues a e highe han 70 % o he con ol
cell iabili y, and he e o e i can be conside ed ha hey a e no
cy o oxic [72]. In e es ingly, he ma e ials induced he elease o LDH,
which is used o de e mine cellula oxici y (p <0.0001). LDH is
eleased om damaged cells. The ob ained esul s, app oxima ely 25 %
LDH elease, a e in line wi h he esul s ob ained p e iously o high
molecula weigh PCL implan s p epa ed using a simila me hod [28].
Al e na i ely, he me abolic ac i i y ob ained in he ea ed cells is
signi ican ly lowe han he con ol (p =0.009). Howe e , he esul s
ob ained in he cell iabili y and cell p oli e a ion (p =0.069) indica e
ha he esul ing ma e ials a e no cy o oxic.
4. Conclusion
The in anasal implan s con aining RIS we e success ully ab ica ed
and cha ac e ised in his s udy. The implan consis ed o wo pa s: a
co e laye p epa ed om RIS and wa e -soluble polyme s (PVP and
PEG), and a coa ing laye made o PCL ilm. RIS was homogenously
dis ibu ed wi hin he co e implan . Mo eo e , he mal analysis and
FTIR esul s sugges ed in e ac ions be ween RIS and he wo wa e -
soluble polyme s. Fu he mo e, he in i o elease p o ile o RIS
showed ha he coa ing laye made o PCL ilm could ex end he elease
o RIS om 2 days up o 100 days. No ably, he pe o med ese oi - ype
implan exhibi ed a linea elease o e he i s 10 days, ollowed by a
slowe elease a e ha eached ano he linea phase up o 40 days.
Subsequen ly, he d ug elease a es p og essi ely slowed down. Mo e-
o e , a single implan was able o p o ide sus ained d ug elease o
he apeu ically ele an RIS dose in i o. The cy o oxici y s udy o he
implan showed ha he in anasal implan s we e biocompa ible and
non- oxic o he es ed model cells (HDF). Acco dingly, he indings om
his s udy sugges ha he implan s ha e he po en ial o p o ide long-
ac ing d ug deli e y o a ge ing he b ain. The e o e, u he s udies,
such as in i o pha macokine ic and biodis ibu ion s udies using sui -
able animal models, a e equi ed o e alua e he deli e y o RIS om
his in anasal implan able de ice o he b ain. Addi ionally, s udies
ela ed o sa e y, s e ili y, and s abili y should be conduc ed p io o
clinical applica ion.
CRediT au ho ship con ibu ion s a emen
Emilia U omo: W i ing –o iginal d a , Valida ion, Me hodology,
In es iga ion, Fo mal analysis, Da a cu a ion, Concep ualiza ion. Jiaqi
Gao: In es iga ion. Qoni a Ku nia Anjani: W i ing – e iew &edi ing,
W i ing –o iginal d a . Camila J. Picco: In es iga ion. Na alia Mo -
eno-Cas ellanos: W i ing – e iew &edi ing, Me hodology, In es iga-
ion, Da a cu a ion. Ryan F. Donnelly: Supe ision, Resou ces, Funding
acquisi ion. Juan Domínguez-Robles: W i ing – e iew &edi ing,
W i ing –o iginal d a , Supe ision. Eneko La a˜
ne a: W i ing – e-
iew &edi ing, W i ing –o iginal d a , Supe ision, Resou ces, Fund-
ing acquisi ion, Concep ualiza ion.
Decla a ion o compe ing in e es
The au ho s decla e ha hey ha e no known compe ing inancial
Fig. 5. Cell iabili y, me abolic ac i i y, LDH assay, and cell p oli e a ion es s o PCL-based memb anes (means +S.D., n ≥3).
E. U omo e al.
Jou nal o D ug Deli e y Science and Technology 99 (2024) 105973
8
in e es s o pe sonal ela ionships ha could ha e appea ed o in luence
he wo k epo ed in his pape .
Da a a ailabili y
Da a will be made a ailable on eques .
Acknowledgmen s
EU would like o acknowledge he Indonesian Endowmen Fund o
Educa ion (Lembaga Pengelola Dana Pendidikan/LPDP). EL would like
o acknowledge he Academy o Medical Sciences (SBF005 1011) and
EPSRC (EP/X525625/1) o hei inancial suppo o his wo k. JDR
acknowledges G an RYC-2021-034357-I, unded by MCIN/AEI/
10.13039/501100011033 and by he “Eu opean Union Nex Gene -
a ionEU/PRTR".
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