(M1430-02-09) Co-solvents for Microemulsion Formulations containing Ethoxylated Castor Oils for Transdermal Drug Delivery

Purpose: Transdermal drug delivery provides a non-invasive inexpensive method to administer low molecular weight drugs through the skin. This route is limited by the dosage rates partly because of the solubility of the drug in the formulations. Typically, two formulation types are used in this methodology: kinetically stabilized emulsions and thermodynamically stable microemulsions (MEs). The latter system is formed through spontaneous self-assembly of surfactants and co-surfactants to minimize unfavorable interactions between oil and water phases. MEs enable greater drug loadings and enhance penetration of the drug molecules through the stratum corenum. In this poster, we study the water-in-oil (W/O) ME phase behavior of ethoxylated castor oils (ECO) with a variety of glycol ether co-solvents (CoS) to identify candidates that provide large 1-phase windows, which are desirable for the application. These phase diagrams help select CoS candidates based on drug class to access composition windows of formulation to maximize drug solubility.

Methods: High-throughput formulations of microemulsions were done using an automated liquid handler. A calibration curve between the mass and volume dispensed for each liquid was developed. The dispense parameters for the individual components were also optimized to ensure reproducible delivery of materials, especially for the high viscosity liquids. The ethoxylated castor oils (ECO) were were added clear at 55-60 °C for easy pipetting . Isopropyl palmitate (IPP) was used as the oil phase for all phase diagrams. The ratio of surfactants ECO to glyceryl oleate was held constant at 2:1, and the ratio of co-surfactants to total surfactant content (ECO + glyceryl oleate) was fixed at 0.6. Prerequisite amount of all components except water were added to 1 mL vials and mixed via mechanical shaking for 45 mins. Next, water was added, and the samples were mechanically agitated for 45 min, followed by sonication in a water bath at 40 °C for 90 mins and mixed again by shaking for 30 mins. The samples were allowed to rest for at least 2 h before image acquisition. Images were acquired through our in-house imaging station and phase analyses was performed to identify compositions that yield stable 1-phase microemulsions. Desirable 1-phase windows (marked blue in the figure) were quantified by generating ternary phase diagrams for the various co-solvents. Drug delivery characteristics of liquid microemulsion samples containing 52-54% isopropyl palmitate, 35-37% glyceryl oleate + ECO, 6-10 % H2O, and 2.5% lidocaine base was studied using Franz cells. The jacketed cells with receiver volume of 12 mL (V_reciever) and area of diffusion of 1.767 cm² were heated to 37 °C using a circulating water bath. A synthetic polysulfone membrane (0.45 µm thickness) was used as model skin.

Results: We find two glycol ether cosolvents that widen the composition window of stability as compared to commercial poly(ethylene oxide) cosolvents (see Figure). The solvents are effective in yielding 1-phase composition large windows with three different ethoxylated castor oils, where one of the products contains a hydrogenated hydrophobic tail. This suggests that the cosolvents can be used with other ethoxylated surfactants to obtain MEs for drug delivery. Additionally, drug diffusion studies using a Franz cell show that the candidate solvents do not hinder drug diffusion and afford fluxes comparable to control formulation. We rationalize the observed behavior due to the localization of the co-solvents at oil-water interface, causing flattening of the interface, allowing for a larger water domains and hence wider 1-phase microemulsion composition windows.

Conclusion: Ternary phase diagrams were generated with a variety of glycol ether solvents and ethoxylated castor oils using high-throughput formulation and image acquisition and analyses tools. We identify two cosolvents that afford exceptionally large 1-phase microemulsion windows with three ethoxylated castor oils in water/isopropyl palmitate formulations, which are advantageous for transdermal drug delivery. The formulations also show acceptable drug diffusion characteristics as measured by Franz cell. This study can be extended to explore the effectiveness of the cosolvents with other surfactants to obtain 1-phase microemulsions to maximize drug solubilization.

References: 1. Ethier, A.; Padam;, B.; Baxter, J.; Langley, N.; Richardson, N.; Patel, A. M., The Role of Excipients in the Microstrucutre of Topical Semisolid Drug Products. In The Role of Microstrucutre in Topical Drug Product Development, Langley, N.; Michniak-Kohn, B.; Osborne, D., Eds. Springer: Cham, Switzerland, 2019; Vol. 36.
2. Sintov, A. C.; Shapiro, L., New microemulsion vehicle facilitates percutaneous penetration in vitro and cutaneous drug bioavailability in vivo. Journal of Controlled Release 2004, 95 (2), 173-183.
3. Hosmer, J.; Reed, R.; Bentley, M. V. L. B.; Nornoo, A.; Lopes, L. B., Microemulsions Containing Medium-Chain Glycerides as Transdermal Delivery Systems for Hydrophilic and Hydrophobic Drugs. AAPS PharmSciTech 2009, 10 (2), 589-596.
4. Knop, K.; Hoogenboom, R.; Fischer, D.; Schubert, U. S., Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives. Angewandte Chemie International Edition 2010, 49 (36), 6288-6308.

Ternary phase diagram for water/isopropyl palmitate mixtures with ethoxylated castor oil and tetraethylene glycol as the cosolvent. The blue points correspond to equillibrium 1-phase microemulsions and the borders are drawn to guide the eye. The red points correspond to multiphase emulsion systems, which are thermodynamically unstable.

Ternary phase diagram for water/isopropyl palmitate mixtures with ethoxylated castor oil and two glycol ether as cosolvents. The blue points correspond to 1-phase microemulsions and the borders are drawn to guide the eye. The red points correspond to multiphase emulsion systems, which are thermodynamically unstable. The 1-phase composition window, area under blue shading, is much larger with these cosolvents as compared to tetraethylene glycol.