J Korean Med Sci.  2023 May;38(17):e135. 10.3346/jkms.2023.38.e135.

Injectable Poloxamer Hydrogel Formulations for Intratympanic Delivery of Dexamethasone

• Le TP
• Yu Y
• Cho IS
• Suh EY
• Kwon HC
• Shin SA
• Park YH
• Huh KM

• KMID: 2542023
• DOI: http://doi.org/10.3346/jkms.2023.38.e135

Abstract

Background
In this study, we prepared and evaluated an injectable poloxamer (P407) hydrogel formulation for intratympanic (IT) delivery of dexamethasone (DEX).
Methods
DEX-loaded P407 hydrogels were characterized in terms of thermogelation, drug loading capacities, particle size, and drug release. The in vivo toxicity and drug absorption of the DEX-loaded P407 formulation after IT injection were evaluated using an animal model by performing histopathological analysis and drug concentration measurements.
Results
The P407 hydrogel effectively solubilized hydrophobic DEX and demonstrated a sustained release compared to the hydrophilic DEX formulation. The in vivo study showed that the hydrogel formulation delivered considerable drug concentrations to the inner ear and displayed a favorable safety profile without apparent cytotoxicity or inflammation.
Conclusion
P407 hydrogel can be useful as an injectable inner ear delivery formulation for hydrophobic drugs due to their biocompatibility, drug-solubilizing capacity, thermogelation, and controlled release.

Keyword

Poloxamer; Dexamethasone; Injectable Hydrogel; Intratympanic Injection; Inner Ear Delivery

Figure

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  Fig. 1 Schematic illustration of (A) preparation and (B) intratympanic injection of DEX-loaded P407 hydrogel formulation.DEX = dexamethasone, P407 = poloxamer 407, PEO = poly(ethylene oxide), PPO = poly(propylene oxide).

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  Fig. 2 Solubility of dexamethasone as a function of P407 concentration.P407 = poloxamer 407.

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  Fig. 3 Physical status characterization of DEX-loaded P407. Particle size distribution of (A) P407 and (B) P407-DEX at concentration of 1% w/v in phosphate buffered saline (pH 7.4), measured by dynamic light scattering. (C) Differential scanning calorimeter thermograms and (D) powder X-ray diffraction patterns of DEX, P407, and P407-DEX.DEX = dexamethasone, P407 = poloxamer 407.

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  Fig. 4 The sol-gel transition behavior. (A) Sol-gel transition images of P407, P407-DSP, and P407-DEX at 20°C and 37°C, respectively. Temperature-dependent rheological behavior of (B) P407, (C) P407-DSP, and (D) P407-DEX.DSP = dexamethasone sodium phosphate, DEX = dexamethasone, P407 = poloxamer 407.

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  Fig. 5 In vitro drug release profiles of DSP, DEX, P407-DSP and P407-DEX.DSP = dexamethasone sodium phosphate, DEX = dexamethasone, P407 = poloxamer 407.

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  Fig. 6 Evaluation of in vivo drug uptake. (A) DEX concentration in the intracochlear perilymph of DSP, P407-DSP and P407-DEX group after IT injection at 30 minutes, 90 minutes, 3 hours, 1 day, 3 days and 7 days after treatment. (B) Distribution of DEX in the cochlear tissue in DSP, P407-DSP and P407-DEX. Tissues were stained for DEX (red) and cell nucleus (blue) for assessing DEX uptake. Scale bar = 500 µm. (C) Quantitative analysis of DEX uptake in DSP, P407-DSP and P407-DEX at 30 minutes; 90 minutes and 1 day after IT injection.DEX = dexamethasone, DSP = dexamethasone sodium phosphate, P407 = poloxamer 407. *P < 0.05.

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  Fig. 7 Evaluation of in vivo safety. (A) Sectional histopathologic findings of the middle ear mucosa in normal (left), 7 days after P407-DSP injection (middle) and 7 days after P407-DEX injection (right). Scale bar =50 μm. (B) Whole-mount of auditory epithelium in normal, 7 days after P407-DSP injection and P407-DEX injection. Tissues were stained for myosin-VIIa (red), rhodamine Phalloidin (green) to visualize hair cells and actin and then merged with the myosin-VIIa and rhodamine phalloidin. Scale bar = 50 μm.DSP = dexamethasone sodium phosphate, DEX = dexamethasone, P407 = poloxamer 407, OHC = outer hair cell, IHC = inner hair cell.

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