(W1030-03-13) Role of Polyethylene Glycol and Propylene Glycol in Modulating the Spreadability and 3-D Structure of a Carbomer Based Nasal Gel

Purpose: The study is aimed at formulating a topical nasal gel and rheological evaluation of concentration of carbomer homopolymer type B (Carbopol 974P^TM), polyethylene glycol (PEG) levels, and propylene glycol (PG) as other excipients. The novelty of this study aims to delineate the interactions of poly hydroxyl groups present on the allyl chains of carbomer with PEG & PG and spreadability of the gel in the nasal cavity by application processes including use of an applicator, users’ finger or pressing the wings of the nostrils upon gel introduction. The interaction was evaluated measuring frequency sweeps and yield curves to study gel structure breakage upon stress and ease of spreading at high shear rates. In addition, further understanding of interaction chemistry of the secondary viscosity modulators (PEG & PG) with primary viscosity modifier carbomer influencing the three-dimensional (3-D) structure of the gel at low and high shear rates. An understanding of this dynamics aids in modulating spreadability parameters of topical gels with optimized additive levels, along with applicator induced forces, which would lead to achieving matrix-based modified release of actives for local and systemic release of actives chosen for nasal delivery.

Methods: Translucent nasal gels made with carbomer and other functional excipients required to formulate a complete nasal product. To evaluate influence of additive concentrations of excipients and their influence on spreadability factor of the topical gel a full factorial Design of experiment was planned with varying concentrations of carbomer, polyethylene glycol and propylene glycol. In addition an active material was added along with benzalkonium chloride (preservative), a low molecular weight PEG as emollient and sodium hydroxide as neutralizing agent. The bulk of the vehicle was water at 76 – 84% w/w. After manufacture of the gels, a frequency sweep was conducted on the Anton Paar 570 rheometer starting from a low static shear of 13.4 rad/sec to a high shear of 295 rad/sec. A mixture design to study the influence of the ratios of the secondary viscosity modulators PEG 3350, PEG 400 and propylene glycol on the spreadability of the gel and their interaction dynamics between themselves and the carbomer. A frequency sweep and a yield stress study was performed to evaluate influence of these additives on the 3-D structure of the crosslinked polymer.

Results: The frequency sweeps of the factorial design formulations showed that the carbomer concentration played the major role in contributing to the structure of the gel at low shear rates (13.4 rad/s) (Figure 1). The propylene glycol was shown to contribute to fluidity of the gels at low shears but at a very low impact at the concentrations of 3% to 6% that were studied. At high shears however, the major contributor to the viscosity was propylene glycol. Carbomer and PEG 3350 concentrations were found to have a fluidizing effect to the gel structure at high shear rates. Strong interaction of propylene glycol with carbomer and PEG 3350 could be an explanation for the inverse relationship of the concentration of these polymers and the viscosity at high shears. The mixture designs showed a similar role played by PEG 3350 and propylene glycol as was observed in the factorial design. The ternary plots showed that PEG 3350 showed to play a greater role in structure of the gel at low shear rates but was found to liquify the gel at higher shear rates (295rad/s) (Figure 2). Propylene glycol too showed to contribute to the viscosity at the higher shear rate but was found to add fluidity to the gel at 13.4 rad/s. (Figure 3). A study of the yield stresses of the gel showed a projected result where PEG 3350 was found to elevate the yield stress whereas propylene glycol and PEG 400 were found to reduce the yield force to break the gel structure.

Conclusion: This study highlights the application of rheological testing of nasal gel applications to achieve an easy to apply modified release depot. The spreadability and the 3-D structure of the matrix was contributed mainly by the crosslinked carbomer chains and its interaction with mucin in nasal mucus layer at low shear forces of application. The role of the secondary viscosity modifiers especially at the higher shear rates experienced during the application and spreading would be essential in understanding the efficiency of gel spread and tissue contact. Carbomer and PEG 3350 were found to be essential in imparting structure and body to the gel at low shear rates. The propylene glycol in the gel was predominantly responsible for the viscosity and hence spreadability at high shear rates. The carbomer and PEG 3350 were also found to reduce the viscosity at these high shear rates and contributed to easy spreading. Further studies will be conducted in optimizing the intrinsic rheological properties of this formulation and study the influence on drug release from the nasally applied gel.


Figure 1 Impact of Carbopol and propylene glycol on complex viscosity at shear rate of 13.4 rad/s.


Figure 2: Ternary phase plots of complex viscosity against concentration ratios of PEG 3350, PEG 400 and propylene glycol at low shear.


Figure 3: Ternary phase plots of complex viscosity against concentration ratios of PEG 3350, PEG 400 and propylene glycol at high shear.