Development of innovative in situ forming gels for topical ophthalmic delivery

doctoral thesis

• Title (croatian): Razvoj inovativnih in situ gelirajućih pripravaka za topikalnu primjenu oftalmičkih lijekova
• Author: Iva Krtalić
• Mentor: Jasmina Lovrić (mentor)
• Committee member: Jelena Filipović-Grčić (predsjednik povjerenstva)
• Committee member: Branka Zorc (član povjerenstva)
• Committee member: Marijana Erceg (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of pharmaceutical technology); Zagreb
• Defense date and country: 2018-12-04, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

The anatomical barriers and the tear fluid dynamics in the precorneal area have a huge effect on the eye-related drug
bioavailability. In situ forming gels stand out as the formulation candidates for the improvement of bioavailability
and efficacy of topical ophthalmic drugs. These are prepared as liquid dosage forms that undergo phase transition on
eye surface to form viscoelastic gel in response to an environmental stimulus following topical administration.
During formulation development, in situ forming ophthalmic gels need to be fine-tuned considering all the
biopharmaceutical challenges of the front of the eye. The aim of this thesis was to develop temperature-responsive in
situ forming poloxamer P407/ poloxamer P188/chitosan gel fine-tuned in terms of polymer content, temperature of
gelation and viscosity by applying Quality by Design principles. Minimizing the total polymer content, while
retaining the advantageous rheological properties, has been achieved by means of D-optimal statistical design. In situ
forming gels were prepared by cold method and analyzed by rheological temperature sweep test. Statistical software
was used to set experimental design, establish the mathematical model and analyze the collected data. Validated
mathematical models enabled the selection of 4 candidates of poloxamer 407/poloxamer 188/chitosan systems,
which viscoelastic behavior was studied in depth by oscillatory rheological tests under biorelevant conditions. The
optimal in situ forming gel was selected based on minimal polymer content, favorable rheological characteristics and
in vitro resistance to tear dilution. The formulation robustness against entrapment of active pharmaceutical
ingredients (API) with different physicochemical characteristics was demonstrated using four APIs in the
concentrations and combinations relevant for topical ophthalmic use. Through discriminative in vitro release test,
adequate release profile of model drug was proven. Biocompatibility of the optimal in situ forming gel was
confirmed employing 3D corneal epithelial cell models. In conclusion, a systematic approach to in situ forming gel
development implemented in this thesis resulted in a stable and robust formulation characterized by ease of
formulation preparation, ability for sterile filtration and autoclaving, ease of administration, accuracy of dosing,
avoidance of eye-related discomfort, biocompatibility and prolonged residence at the eye surface.

Abstract (croatian)

Pri primjeni kapi za oko, zbog dinamičnih barijera prekornealonog područja, dolazi do brze eliminacije lijeka s
površine oka. In situ gelovi predstavljaju jedno od inovativnih rješenja suvremene farmaceutske tehnologije za
poboljšanje terapijske učinkovitosti topikalnih oftalmičkih lijekova. Takvi su sustavi oblikovani kao otopina lijeka,
pogodna za topikalnu primjenu, a koja gelira izlaganjem fiziološkim uvjetima. In situ oftalmički gelovi trebaju biti
pomno dizajnirani s ciljem produljenja vremena zadržavanja lijeka na mjestu primjene, povećanja bioraspoloživosti i
učinkovitosti. Cilj je ovoga doktorskoga rada bio razviti in situ gel za oftalmičku primjenu korištenjem smjese
polimera (poloksamera P407, poloksamera P188 i kitozana) specifično dizajnirane u smislu ukupnoga sadržaja
polimera, temperature geliranja (Tgel), kompleksne viskoznosti (η*) i reološkoga parametra modula pohrane (G').
Korištenjem D-optimalnoga statističkoga eksperimentalnog dizajna optimirana su reološka svojstava razvijenih
sustava uz smanjenje ukupne koncentracije korištenih polimera. In situ oftalmički gelovi poloksamera pripravljeni su
''hladnom'' metodom te analizirani reološkim testom promjene temperature. Statistički je softver korišten za
postavljanje eksperimentalnoga dizajna, utvrđivanje modela, generiranje sekvenci i za statističku obradu prikupljenih
podataka. Temeljem validiranih modela, odabrana su četiri vodeća poloksamer 407/poloksamer 188/kitozan sustava,
čije je viskoelastično ponašanje ispitano u detaljnoj reološkoj karakterizaciji. S obzirom na najmanji udio polimera,
poželjna reološka svojstva te in vitro rezistentnost na razrjeđenje suznom tekućinom, miješani je sustav PL1 odabran
kao optimalni in situ gel. Prikladnost razvijenoga sustava kao platforme za uklapanje djelatnih tvari različitih
fizikalno-kemijskih svojstava je dokazana je dodatkom četiri djelatne tvari u koncentracijama i kombinacijama
relevantnim za topikalnu oftalmičku primjenu. Odgovarajući profil oslobađanja djelatne tvari iz PL1 platforme
pokazan je diskriminatornom in vitro metodom oslobađanja. Biokompatibilnosti PL1 optimalnoga in situ gela
pokazana je na 3D epitelnim modelima rožnice. Sustavan pristup razvoju in situ gela, proveden u sklopu
doktorskoga rada, rezultirao je stabilnom i robusnom formulacijom, koju karakterizira jednostavna priprava,
mogućnost sterilizacije te svojstva koja omogućuju jednostavnost primjene, točnost doziranja, izbjegavanje nelagode
nakon primjene, biokompatibilnost i produljeno zadržavanje na površini oka.

• Keywords: ophthalmic drug delivery; quality by design (QbD); poloxamers; chitosan; rheology; temperatureresponsive in situ forming gel; temperature of gelation
• Keywords (english): oftalmička primjena; kvaliteta uključena u dizajn (eng. QbD); poloksameri; kitozan; reologija; geliranje uzrokovano povećanjem temperature; temperatura geliranja
• Language: english
• URN:NBN: urn:nbn:hr:163:959202
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2019-04-04 15:18:43