The main inconvenience of conventional eye drops is the rapid washout of the drugs due to nasolacrimal drainage or ophthalmic barriers. The ocular drug bioavailability can be improved by either prolonging retention time in the cul-de-sac or by increasing the ocular permeability. The focus of this review is to highlight some chitosan-based drug delivery approaches that proved to have good clinical efficacy and high potential for use in ophthalmology. They are exemplified by recent studies exploring in-depth the techniques and mechanisms in order to improve ocular bioavailability of the active substances. Used alone or in combination with other compounds with synergistic action, chitosan enables ocular retention time and corneal permeability. Associated with other stimuli-responsive polymers, it enhances the mechanical strength of the gels. Chitosan and its derivatives increase drug permeability through the cornea by temporarily opening tight junctions between epithelial cells. Different types of chitosan-based colloidal systems have the potential to overcome the ocular barriers without disturbing the vision process. Chitosan also plays a key role in improving corneal wound healing by stimulating the migration of keratinocytes when it is used alone or in combination with other compounds with synergistic action.

Ocular in situ gels are a promising alternative to overcome drawbacks of conventional eye drops because they associate the advantages of solutions such as accuracy and reproducibility of dosing, or ease of administration with prolonged contact time of ointments. Chitosan is a natural polymer suitable for use in ophthalmic formulations due to its biocompatibility, biodegradability, mucoadhesive character, antibacterial and antifungal properties, permeation enhancement and corneal wound healing effects. The combination of chitosan, pH-sensitive polymer, with other stimuli-responsive polymers leads to increased mechanical strength of formulations and an improved therapeutic effect due to prolonged ocular contact time. This review describes in situ gelling systems resulting from the association of chitosan with various stimuli-responsive polymers with emphasis on the mechanism of gel formation and application in ophthalmology. It also comprises the main techniques for evaluation of chitosan in situ gels, along with requirements of safety and ocular tolerability.

This chapter focuses on the eye, one of the most important organs of humans. Current data on pathophysiology of the human eye are presented in direct correlation with a range of therapeutic products, with a well-known and widely used material, namely chitosan. Applications of chitosan biopolymer are described in the development of innovative, modern, therapeutic devices and solutions. Thus, chitosan is a good excipient either for classic drop-type ocular systems, as well as for complex drug systems such as nanostructures (nanoparticles, nanomicelles and nanosuspensions), liposomes, microemulsions, microspheres, in situ hydrogels and inserts or implants. A number of disadvantages for ocular administration of the drugs are thus overcome.

The aim of this paper was the formulation and preliminary evaluation of colloidal systems with improved mechanical and mucoadhesive properties in order to increase ocular retention time and drug bioavailability. Polymeric mixtures of chitosan (0.3%), a pH-sensitive polymer, and poloxamer 407 (12%, 15%, 18%), thermoresponsive polymer, with bupivacaine hydrochloride (0.25%) were prepared. Gelling temperature, wettability, rheological behaviour and in vitro drug release were evaluated. The formulation containing 15% poloxamer 407 is converted to a colloidal dispersion at 35°C, the temperature of the ocular surface. Contact angle values of colloidal systems at physiological temperature (35°C) were lower than those corresponding to formulations at non-physiological temperature (25°C), indicating a higher spreadability over the ocular surface. Rheological studies have shown pseudoplastic behaviour and the poloxamer concentration increased the viscosity of the formulations. In vitro bupivacaine hydrochloride delivery from colloidal systems revealed that drug release mechanism followed Higuchi model. The colloidal dispersions with chitosan and poloxamer 407 could be viable alternatives to increase the bioavailability of bupivacaine hydrochloride in topical ocular anaesthesia. Rezumat Obiectivele acestei lucrări sunt formularea şi evaluarea preliminară a unor sisteme coloidale cu proprietăţi mecanice şi mucoadezive sporite care să asigure un timp de remanenţă crescut la nivel ocular şi o biodisponibilitate a substanţei medicamentoase îmbunătăţite. S-au preparat amestecuri polimerice de chitosan (0,3%), un polimer sensibil la variaţia de pH, şi poloxamer 407 (12%, 15%, 18%), polimer cu proprietăţi termoreversibile, în care a fost încorporată bupivacaină clorhidrat (0,25%). Pentru acestea s-au evaluat: temperatura de gelifiere, udabilitatea, comportamentul reologic şi cedarea in vitro a substanţei active. Formularea conţinând 15% poloxamer 407 s-a transformat într-o dispersie coloidală la 35°C, temperatura de la suprafaţa oculară. Valorile unghiurilor de contact pentru sistemele coloidale la temperatura fiziologică (35°C) au fost mai mici decât cele corespunzătoare formulărilor la temperatura nefiziologică (25°C), fapt ce indică o etalare corespunzătoare pe suprafaţa oculară. Studiile reologice au arătat un comportament pseudoplastic, iar la creşterea concentraţiei de poloxamer s-a înregistrat creşterea vâscozităţii preparatelor. Cedarea in vitro a bupivacainei clorhidrat din sistemele coloidale s-a realizat în conformitate cu modelul Higuchi. Dispersiile coloidale de chitosan şi poloxamer 407 pot reprezenta alternative viabile de creştere a biodisponibilităţii bupivacainei clorhidrat în anestezia topică oculară.

The aim of this study was the development and optimization of chitosan and hydroxypropyl methylcellulose (HPMC) in situ gelling systems, loaded with bupivacaine hydrochloride for topical ocular administration. This study is based on the properties of two polymers: chitosan, which has mucoadhesive action and is a pH-sensitive polymer, but also the cellulose derivative hydroxypropyl methylcellulose, a thermosensitive polymer which has mucoadhesive properties and increases the viscosity of systems. The analysis and optimization of in situ gelling systems were performed based on an experimental design and response surface methodology. The following formulation parameters were considered: X1 = chitosan concentration (0.5%, 1%), X2 = HPMC E 5 LV concentration (2%, 5%) and X3 = Chitosan/HPMC E 5 LV ratio (1/1, 2/1). In addition, the parameters to be optimized were represented by the contact angle (CA (°)), viscosity and cumulative percentage of bupivacaine hydrochloride released in vitro. The results indicate that the designed in situ gelling systems are suitable for bupivacaine prolonged ophthalmic release and overcome the principal disadvantages of the liquid’s ocular formulations. An immediate therapeutic effect corresponding to ocular anesthetic installation was assured in the first stage: burst bupivacaine release. In the second phase, the gradual drug release was assured for over 6 h. This drug release profile, together with the corresponding rheological profile and a collection of superficial properties for good ocular adhesion balanced with an adequate hydrophilic character, assured the desired quality of the attributes for the proposed systems. The system, based on chitosan 1%, HPMC E 5 LV 5% and a 1/1 polymer ratio, could be a solution for the proposed formulation of in situ gelling colloidal systems, since the viscosity of the system was within the range of the optimal viscosity of the eye, and the amount of bupivacaine hydrochloride released after 6 h was the highest at 69.55%.