Development and Optimization of A Hesperetin–Hp- Β -Cyclodextrin Hydrogel for Topical Delivery: Formulation Optimization, Release Kinetics and Stability Evaluation
Keywords:
Hesperetin, HP-β-CD, Carbopol 934P, topical hydrogel, Box–Behnken design, formulation optimization, drug release, Higuchi model, Korsmeyer–Peppas model, stabilityAbstract
Background: Hesperetin is a poorly water-soluble flavanone with limited pharmaceutical availability, which may restrict
its effective incorporation into topical dosage forms. Cyclodextrin complexation followed by incorporation into a polymeric
hydrogel may provide a sequential approach to improve its formulation performance and regulate drug release. The present
study aimed to develop and optimize a Hesperetin–hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion-complex-loaded
Carbopol 934P hydrogel using a systematic design of experiments approach.
Methods: A three-factor, three-level Box–Behnken design was employed to investigate the effects of Carbopol 934P
concentration (0.5–1.0%), Hesperetin–HP-β-CD inclusion-complex concentration (2.0–4.0% w/w), and propylene glycol
concentration (5–15%) on pH, viscosity, spreadability, drug content, and cumulative drug release at 8 h. Seventeen
experimental formulations were prepared and evaluated. Quadratic response-surface models were fitted, followed by multiresponse desirability-based optimization. The optimized formulation was independently validated and further evaluated for
physicochemical characteristics, swelling behavior, comparative in-vitro drug release, release kinetics, antioxidant activity,
and accelerated stability.
Results: The experimental formulations showed pH values of 5.53–5.76, viscosity of 10,785–23,876 cP, spreadability of
6.51–8.06 g·cm/s, drug content of 95.74–99.07%, and 8-h drug release of 76.19–93.76%. Formulation F9 was selected as
the optimized formulation, containing 0.75% Carbopol 934P, 4.0% w/w Hesperetin–HP-β-CD inclusion complex, and 15%
propylene glycol, with a composite desirability of 0.942. The predicted responses were pH 5.64, viscosity 17,086 cP,
spreadability 7.42 g·cm/s, drug content 97.92%, and 8-h release of 88.32%. Independent validation yielded pH 5.65 ± 0.01,
viscosity 17,016.7 ± 116.8 cP, spreadability 7.41 ± 0.04 g·cm/s, drug content 97.68 ± 0.16%, and 8-h drug release of 88.32
± 0.23%, with prediction errors below 0.5%. The optimized hydrogel exhibited progressive swelling and drug release. In the
extended-release dataset, drug release reached 80.4% at 8 h and 91.2% at 12 h. The Higuchi model showed a high correlation
(R² = 0.9969), while the Korsmeyer–Peppas model provided a complementary empirical fit (R² = 0.9998; n = 0.8702). DPPH
radical-scavenging activity increased with increasing concentration. Accelerated stability evaluation at 40 ± 2 °C/75 ± 5%
RH demonstrated only minor changes in pH, drug content, and drug release over three months.
Conclusion: The findings demonstrate the feasibility of a sequential Hesperetin–HP-β-CD inclusion-complex-to-hydrogel
strategy for developing a topical formulation with improved pharmaceutical availability and regulated drug release. The
optimized Carbopol 934P hydrogel exhibited reproducible formulation characteristics, progressive drug release,
concentration-dependent antioxidant activity, and short-term accelerated stability. Further studies involving longer-term
stability, skin deposition, cytocompatibility, and appropriate biological evaluation are warranted.
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