QbD Design, Formulation, Optimization and Evaluation of Trans-Tympanic Reverse Gelatination Gel of Norfloxacin: Investigating Gene-Gene Interactions to Enhance Therapeutic Efficacy

Traditional otic drug delivery methods lack controlled release capabilities, making reverse gelatination gels a promising alternative. Reverse gelatination gels are colloidal systems that transition from a sol to a gel phase at the target site, providing controlled drug release over an extended period. Thermosensitive norfloxacin reverse gelatination gels were developed using a Quality by Design (QbD)-based optimization approach. The formulations were evaluated for their in vitro release profile, rheological behavior, visual appearance, pH, gelling time, and sol–gel transition temperature. The results show that the gelation temperatures of the formulations ranged from 33 to 37 °C, with gelling durations between 35 and 90 s. The drug content in the formulations was uniform, with entrapment efficiency ranging from 55% to 95%. Among the formulations, F10 exhibited the most favorable properties and was selected for a stability study lasting 60 days. Ex-vivo release data demonstrate that the F10 formulation achieved 95.6percentage of drug release at 360 min. This study successfully developed thermosensitive norfloxacin reverse gelatination gels using a QbD-based optimization approach. The selected formulation, F10, exhibited desirable properties in terms of gelling temperature, drug content, and release profile. These gels hold potential for the controlled delivery of norfloxacin in the treatment of ear infections.

4.2. Selection of Polymer

The formulation of the norfloxacin in situ gel involves the careful selection of polymers to achieve desired properties and drug delivery characteristics. Three key polymers, namely, poloxamer-407, carbopol-940, and hydroxypropyl methyl cellulose (HPMC), were chosen for their specific roles in the gel formulation.

Each polymer contributes unique properties, allowing for the successful development of an effective norfloxacin in situ gel. (a) Poloxamer-407 is a thermosensitive polymer that undergoes a sol–gel transition in response to temperature changes. At lower temperatures, poloxamer-407 remains in a liquid state, facilitating ease of administration and application. However, upon contact with body heat or affected areas, it undergoes rapid gelation, transforming into a semi-solid gel form. This temperature-triggered gelation is particularly advantageous for the norfloxacin gel, as it provides a favorable solution for topical application, and once applied, it transforms into a stable gel, promoting prolonged contact time with the skin or mucosal surfaces. The gelation behavior of poloxamer-407 eliminates the need for additional chemical cross-linkers, simplifying the formulation process and minimizing potential toxicity concerns.

The inclusion of poloxamer-407 is essential to providing an easy-to-administer and well-adhering norfloxacin gel product. (b) Carbopol-940, also known as carbomer, is a high-molecular-weight synthetic polymer with excellent thickening and gel-forming properties. In the norfloxacin gel formulation, carbopol-940 plays a crucial role in providing the desired consistency, viscosity, and stability. It forms a gel network by swelling in water, which entraps norfloxacin and other excipients, preventing their easy dispersion and ensuring uniform drug distribution within the gel matrix. The addition of carbopol-940 enhances the gel’s mechanical strength and improves drug retention, promoting controlled drug release over an extended period.

The gel’s pseudoplastic flow behavior also facilitates smooth application, as it reduces resistance during spreading and improves patient compliance. Furthermore, carbopol-940’s ability to stabilize the gel formulation helps maintain the integrity of the product during storage and transportation. (c) Hydroxypropyl methyl cellulose (HPMC) is a hydrophilic polymer used as a gelling agent and viscosity modifier in pharmaceutical formulations. In the norfloxacin gel, HPMC complements the properties of poloxamer-407 and carbopol-940. It enhances the gel’s rheological properties, providing pseudoplastic flow behavior that aids in smooth application and ease of spreading. HPMC contributes to the gel’s bioadhesive properties, improving its adhesion to the skin or mucosal surfaces and increasing drug retention time at the application site. This prolonged contact promotes better drug absorption and therapeutic efficacy. Additionally, HPMC’s moisture-retaining properties maintain proper hydration of the gel, ensuring its stability and preventing gel shrinkage or cracking.

The norfloxacin gel was made by putting together poloxamer-407, carbopol-940, and HPMC in a way that takes advantage of their individual properties and creates a synergistic effect. The gelation of poloxamer-407 is triggered by temperature, and the thickening and stabilizing properties of carbopol-940 create an ideal gel matrix that allows controlled drug release and a longer time for the gel to stay in the ear where it is applied. HPMC complements this by enhancing the gel’s flow behavior and bioadhesion, providing better patient comfort and improved drug absorption during in situ gel application. This well-balanced formulation ensures the successful delivery of norfloxacin for effective treatment in otic applications [30].

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Budhori, A.; Tiwari, A.; Tiwari, V.; Sharma, A.; Kumar, M.; Gautam, G.; Virmani, T.; Kumar, G.; Alhalmi, A.; Noman, O.M.; et al. QbD Design, Formulation, Optimization and Evaluation of Trans-Tympanic Reverse Gelatination Gel of Norfloxacin: Investigating Gene-Gene Interactions to Enhance Therapeutic Efficacy. Gels 2023, 9, 657.
https://doi.org/10.3390/gels9080657

excipients formulation