PREPARATION AND EVALUATION OF AZM-THERMOSENSITIVE GELS DESIGNED FOR OPHTHALMIC ADMINISTRATION

GION CHIOSSO ; DANIELA QUINTEROS; CESAR GOMEZ; STRUMIA M.; PALMA S.; CRUZ L.; ALLEMANDI D A.

Rosario

Congreso; 2° Reunión Internacional de Ciencias Farmacéuticas.; 2012

PREPARATION AND EVALUATION OF AZM-THERMOSENSITIVE GELS DESIGNED FOR OPHTHALMIC ADMINISTRATION Gion Chiosso K 3, Quinteros DA 1, Gomez, CG 2, Strumia M 2, Palma SD 1, Cruz L2, Allemandi DA 1• 1 Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba. (UNITEFA-CONICET). Haya de la Torre y Medina Allende. Córdoba (X5000HUA). Argentina 2Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba. (IMVIB-CONICET). Haya de la Torre y Medina Allende. Córdoba (X5000HUA). Argentina 3Departamento de Farmácia Industrial, Universidade Federal de Santa Maria, 97105-900, Santa Maria-RS, Brasil Introduction Acetazolamide (AZM) is a carbonic anhydrase inhibitor used to reduce mainly intraocular pressure in the treatment of glaucoma. However, the low permeability and AZM solubility (0.7 mg/mL) limit its use as a topical formulation. Moreover, eye drops often result in poor bioavailability due to a rapid precorneal drainage, which may be overcome by forming gel in situ. This system is easily reproducible, where the administration of the formulation into the eye as drops leads to a sol-to-gel phase transition in situ on the cornea surface at body temperature. Poloxamer 407 (P407) is a linear tri-block copolymer consisting of a polypropylene oxide block (PPO) between two polyethylene oxide blocks (PEO). The inner PPO core is able to solubilise hydrophobic compounds and hence P407 has application in, for example, the controlled release of ‘water insoluble’ drugs. In this study the influence of the polymer concentration, ionic strength and temperature was evaluated on gel formation and also the release of AZM. Materials and Methods P407 (BASF,Germany), AZM(Parafarm, Argentina). Aqueous solutions at 15 and 17 wt-% of P407 (P40715 or P40717) were prepared using as solvent water or saline (S), and then AZM was solubilized (1or 2 mg/mL) in the formulation (Table 1). Samples were characterized by pH measurements (potentiometer), osmolarility (Osmomat 030-D Cryoscopic) and dynamic rheology assays (Rheoplus MCR301. Anton Paar). Studies of in vitro release were carried out in bicompartimental diffusion cells at 35°C (Franz´s cell). Results and discussion It is known that at a given concentration P407 exists in solution as single entities (unimers), which aggregate above a critical concentration (typically 1% w/v) to form micelles. A longer chain of PPO decreases the critical micelle concentration, with a micellization process also highly temperature dependent. At high concentrations certain triblock copolymers are able to form gels1. Isoosmotic liquid formulations with pH near 7.0 were prepared and characterized by determination of AZM in vitro release rate from formulation with variable AZM concentrations and P407 proportions. (Table 2) shows that all formulations have a sol-gel transition temperature (T sol-gel) when the temperature was varied. The AZM incorporation in formulations P40715 or P40717 produces a decrease in the T sol-gel. The thermosensitive gels P40715 or P40717 containing 1 mg/mL of AZM exhibited a similar release profile, although the latter was slower than that found in the PBS solution. A higher AZM concentration leads to a faster release for P40715. This behavior shows the influence of a hydrophobic drug such as AZM on the gel formation process. P40715 gels have lower viscoelastic properties (Table 2), and drug release delay by diffusion is almost irrelevant. These formulations evidenced a direct relationship between the AZM concentration and its release rate from the gel. Moreover, formulations P40717 prove a similar release rate for both AZM concentrations. This phenomenon is attributed to the fact that this gel has a higher crosslinking density corresponding to noncovalent interactions, which regulates the AZM release by diffusion through gel. Rheology assays displays that P40717 has higher viscoelastic properties, which supports this statement. Conclusion Isoosmotic liquid formulations of P40715 or P40717 were prepared, and then the performance of AZM release in vitro was analyzed for samples with different drug concentrations and ionic strengths. P407 was able to solubilise at 2 mg/mL AZM concentration, whereas drug release kinetic was controlled at 35 ºC by its diffusion through gel when a 17 wt-% of polymer was used. In this condition, the formulations have a crosslinking degree higher than that found in 15ww-%, which is supported by rheology assays. Acknowledgements: CONICET, UNC, UFSM, SECyT-UNC References 1- Peter A. Williams, Handbook of Industrial Water Soluble Polymers, Ed. Blackwell Publishing Ltd (2007), page 84.