Date of Award


Document Type


Degree Name

Philosophy (Ph.D)


Pharmaceutical Sciences

First Advisor

Senshang Lin

Second Advisor

Bhagwan Rohera

Third Advisor

Emilio Squillante


The major barrier for sublingual absorption of large molecules like insulin is low permeability owing to the hydrophilic nature of insulin. One approach to overcome this barrier is to sublingually co-administer insulin with permeation enhancers (HPβCD and poloxamer 188). In vitro performance of permeation enhancers was screened across cellulose acetate membrane to select the concentrations of both enhancers, which were further evaluated across four models (MatTek tissue model, MDCK cell line, rat and porcine esophagus). The insulin solution with combination of HPβCD (5%) and poloxamer 188 (0.5%) indicates higher permeation as compared to that of only insulin across all the four models. Subsequently, porcine esophagus was selected as a tool for in vitro permeation studies for sublingual insulin solution. Furthermore, insulin-induced hypoglycemic effect was observed for insulin solution formulations with combination of HPβCD and poloxamer 188 after sublingual administration to Sprague-Dawley rats. An increase in dose of insulin from 5, 10, and 15 IU/kg along with HPβCD and poloxamer 188, maximum reduction of glucose level increased. After exploring the feasibility of HPβCD and poloxamer 188 for sublingual insulin solution administration, permeation of insulin solution was optimized using three-level resolution III fractional factorial design. In this design, the independent (X1: concentration of insulin; X2: concentration of HPβCD; X3: concentration of poloxamer 188) and dependent (Y: cumulative amount permeated at 60 minutes) variables were used. Based on the generated equation from this design, not only contour and interaction plots were generated but also an optimized formulation, and two checkpoint formulations were obtained to validate the design. Thereafter, insulin at three doses for the optimized formulation and safety of permeation enhancers was evaluated. Based on the optimized sublingual insulin solution, polymeric sublingual films were formulated and evaluated. The sublingual insulin films were found to have comparative mechanical properties to that of commercial film (Listerine®). Based on in vitro dissolution and in vitro permeation, it can be concluded that the film on dissolution could behave like insulin solution and hence is a feasible approach for sublingual administration.

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