(W1030-03-19) Preformulation Study of Poloxamer 407 Formulations for Otic Delivery: The Effect Ear Stimulating Fluid (ESF) and Some Salts on Gelation Characteristics

Purpose: The poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers, known as poloxamer (Pluronic®), are amphiphilic polymers that possess unique thermo-responsive properties with many pharmaceutical and biomedical applications such as the development of drug delivery systems[1]. Though widely exploited in the healthcare sector, they have several characteristics that limit their use in clinical settings such as sol-gel transition above or below the body temperature and poor mechanical properties[2]. Some investigations have been conducted to find various ways of improving these characteristics. These include using different poloxamer blends, hydrophobically-modified poly(acrylic acid) polymers (Carbopols), cellulose-based polymers, Polycarbophil, chitosan, poly(vinyl alcohol), alginates, carrageenan, nanoparticles, salts, solvents, pH controlling agents, and poly(ethylene glycol) [3, 4]. There are varieties of dosage forms that could be improved with Poloxamer gels. For example, for otic delivery to the inner ear, poloxamers could be used to deliver drug molecules to the round window membrane via the intratympanic route novel to overcome the challenge of Eustachian tube drainage. This could potentially reduce the number of doses required and increase patient compliance. In this preformulation study, we investigate the effect of ear-stimulating fluid (ESF) and its individual components on the gel characteristics of Poloxamer 407 (Kolliphor ® P 407 micro Geismer, BASF).

Methods: Different concentrations of Poloxamer were prepared using the cold method with deionized water (DIW) and ESF as solvents. Poloxamer preparations containing 5% of different salts NaCl, NaHCO₃, MgCl₂, CaCl₂, and KCl were prepared and stored at 4℃. Samples were heated gradually at 1℃/min while stirring with a magnetic rod at 30rpm. The temperature at which the magnetic rod stops is recorded as the gelation temperature. For texture profile a Brookfield CT3-1000 Texture Analyzer equipped with an acrylic probe, 1 kg loading cell and a TA-RT Kit was used. The gels were placed on the stationary arm and the probe inserted twice to a 4mm depth with a delay of 30s between the two compressions. TexturePro CT software, V1.4, was used to record various parameters such as hardness, springiness, stringiness work done, and cohesiveness among others. For mucoadhesion tests mucin discs prepared were applied to bottom of the acrylic probe and lowered to the surface of the gelled samples at a rate of 0.5 mm/sec and a hold time of 30 s at the surface of the substrate. The maximum negative detachment force required to separate the mucin disc from the gel surface were recorded as the adhesion force and adhesiveness.

Results: The lowest sol-gel transition temperatures for formulations prepared with deionized water and ear-stimulating fluid were 30.3℃ and 25.1℃ respectively for 20% preparations and the highest (33.7℃ and 32.7℃ for DIW and ESF respectively) for 12.5% preparations. For salt containing formulations, lowest transition temperatures were 17.3℃ for NaCl, 14.2℃ for KCl, 19.7℃ for MgCl₂, 21.6℃ for CaCl₂ and 22.8℃ for NaHCO₃. Highest transition temperatures of 20.0℃ for NaCl, 18.3℃ for KCl, 25.6℃ for MgCl2, 26.9℃ for CaCl₂ and 24℃ for NaHCO₃. For 20% DIW and ESF formulations, (1.606N and 0.913N) were recorded for the first hardness cycle, (0.883N and 0.853N) were recorded for the second cycle of hardness respectively. For Salt containing preparations the highest recorded hardness values for both cycles were recorded for 20% KCl: first cycle (2.435N) and the second cycle (2.39N). The lowest recorded hardness values were 0.374N for the first cycle and 0.354N for the second cycle (12.5% CaCl₂). For DIW and ESF formulations the highest adhesiveness and adhesive forces were recorded for 17.5% and 20% formulations respectively whilst 12.5% of both formulations were the least adhesive. For salt containing preparations, 17.5% CaCl₂ was the most adhesive (0.95mJ adhesiveness and 2.30N adhesive force) whilst 12.5% NaCl was the least adhesive (0.22mJ adhesiveness and 0.25N adhesive force).

Conclusion: Gelation temperature generally increased with decreasing Poloxamer concentration for DIW, ESF and salt-containing formulations. Addition of salt decreased the gelation temperatures to different extents compared to DIW and ESF formulations with KCl being the most effective. Also gel characteristics such as hardness and adhesivesness were significantly modified with the addition of salts. Poloxamer gel characteristics could be modified with salts, or a combination of salts and change of solvents to suit various applications.

References: 1. Mfoafo, K., et al., Contemporary Applications of thermogelling PEO-PPO-PEO triblock copolymers. Journal of Drug Delivery Science and Technology, 2022: p. 103182.
2. Sosnik, A., et al., Crosslinkable PEO-PPO-PEO-based reverse thermo-responsive gels as potentially injectable materials. Journal of Biomaterials Science, Polymer Edition, 2003. 14(3): p. 227-239.
3. Pisal, S.S., et al., Pluronic gels for nasal delivery of Vitamin B12. Part I: Preformulation study. International Journal of Pharmaceutics, 2004. 270(1): p. 37-45.
4. Gratieri, T., et al., A poloxamer/chitosan in situ forming gel with prolonged retention time for ocular delivery. European Journal of Pharmaceutics and Biopharmaceutics, 2010. 75(2): p. 186-193.

Acknowledgements: We acknowledge BASF Corporation for donating Kolliphor P 407 micro Geismer for the experiments

Figure 1. The Mucoadhesion Test Set Up Using a Brookfield CT3-1000 Texture Analyzer and Mucin Disc

Table 1. Results of the Gelation, Mucoadhesion and Texture Profile Tests