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Development of innovative in situ forming gels for topical ophthalmic delivery

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.

ophthalmic drug delivery ; quality by design (QbD) ; poloxamers ; chitosan ; rheology ; temperature responsive in situ forming gel ; temperature of gelation

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