Solution Versus Suspension: How Does the Pharmaceutical Form of Insulin Shape the Mechanical Properties and Release Kinetics of a Carbopol® Ultrez™ 10/Sodium Alginate Hybrid Hydrogel with a Molecular-Docking Rationale for Diffusion-Controlled Deliver

This study aimed to determine how insulin’s pharmaceutical form governs release from a topical matrix and to provide a molecular-level rationale for the observed behavior. A hybrid hydrogel of Carbopol® Ultrez™ 10 and sodium alginate (1:2) was loaded with human insulin in two clinically distinct forms: a soluble solution (Actrapid®) and an isophane/NPH suspension (Insulatard®). Insulin release from the CU10:SA (1:2) hybrid hydrogel is continuous, without any sudden surge in release (the so-called *burst* effect), and follows diffusion according to Fick’s law. The soluble formulation released more insulin than the suspension, although the two profiles were similar in shape (f1 = 13.39; f2 = 97.54). The two CU10/SA insulin hydrogels were pseudoplastic fluids with pronounced shear-stress hysteresis and did not differ in hardness, cohesiveness, adhesiveness, or elasticity. Two rheological models, including the Carreau–Yasuda (CY) model and Santesarti’s shear rate-based model (SRB), described the recorded shear stress vs. shear rate curves fairly well. To explore this behavior at the molecular level, cavity-guided blind docking (CB-Dock2/AutoDock Vina) was performed on both the insulin monomer and the assembled zinc hexamer, using deprotonated oligomer models of the polymers. The alginate and Carbopol fragments converged on a single B-chain surface patch, where a carboxylate–Arg-B22 salt bridge supported by hydrogen bonding appeared to be the main anchoring motif, with weak docking scores (−4.5 to −4.9 kcal/mol on the insulin monomer) indicative of reversible physisorption rather than tight binding; the same patch was also engaged on the hexamer, which suggests that the proposed interaction motif does not depend on the insulin association state. These docking results are hypothesis-generating and complement, rather than prove, the experimental findings. The greater release of soluble insulin is attributed mainly to its pharmaceutical form, since the larger, less mobile protamine–zinc microcrystals of NPH insulin are likely to be more strongly entrapped in the matrix, rather than to differences in interaction chemistry. Together, the results link interaction chemistry, formulation state, and diffusion-controlled release.