(T1530-12-70) In Situ Phase Transition to Liquid Crystal with the GMO and Co-surfactant for Controlled Nasal Mucosa Permeation of Drug

Purpose: Nasal routes of administration are a competent method for drugs to reach the brain. This is because the olfactory region of nasal cavity is directly connected to the central nervous system. Lipid-based Glycerol monooleate(GMO) has desirable properties for intranasal administration as a lipid capable of forming liquid crystal(LC)[1,2]. It has been reported that LC consists of oil, surfactant and water and is being studied as a drug delivery system due to its unique properties. LC has a semi-solid crystal structure that combines solid and liquid properties. Thus, the crystal structure of LC makes the system highly viscous, and this typical property can be used to control the release and absorption of drugs from pharmaceutical product via difference in the diffusion rate According to the concept revealed by Mueller, the concept of in situ phase transition indicates the sustained release rate after contact of the precursor with water[3]. This study was aimed to evaluate the applicability of a sustained release drug delivery system (DDS) using GMO and co-surfactant to produce precursors that undergo a phase transition to LC upon contact with water.

Methods: Donepezil was used as a model drug. Since the LC formation range is narrow when GMO (HLB=3) alone is used alone, a sample is prepared to confirm LC formation in combination with co-surfatant (HLB over 10). GMO and co-surfactant were melted at 40℃ before use. The surfactant, co-surfactant, oil (medium-chain triglyceride (MCT)) and water were combined using the homogenizer for 1 min, then degassed using sonication for 5min. The degassed samples were equilibrated for 18~24hr in shaking water bath. The phase of the sample was confirmed using Polarized light microscopy (PLM). In addition, ex vivo permeation study with porcine nasal mucosa was performed in order to evaluate the permeability of the prepared formulations. J(Permeation flux) and Kp(permeability coefficient) were obtained in this experiment [4].

Results: The ternary phase diagram consisting of (GMO:co-surfactant=9:1) + MCT + Water is shown in Figure 1(a). LC formation points observed through a PLM were indicated by red dots. Figure 1(b) shows a tendency of the phase change in the following order as the proportion of co-surfactant in the surfactant (GMO: co-surfactant) increases at a constant 20% water composition; LC-crude emulsion-microemulsion-LC. The results of ex vivo permeability test presented in Table 1. The effect of two variables of i) surfactant and oil ratio and ii) co-surfactant concentration on the change in permeability can be seen in Figure 2 (a) and (b), respectively. Figure 2(a) shows that the permeation increases as the MCT ratio increases. Since LC is formed only when the MCT ratio is low, the permeation is slow. In addition, it was suggested that the LC type generated depends on the proportion of co-surfactant. It is proposed that this affected the permeation rate, and it is judged that further research is necessary. from Figure 2(b).

Conclusion: This study focused on lipid-based LC DDS for nasal mucosa permeation, which can have sustained release property. Therefore, it was confirmed that LC formation through various composition change can effectively control the drug release permeability

References: 1. See, Gerard Lee; Arce, Florencio; Dahlizar, Sabrina; Okada, Akie; Fadli, Muhammad Fikri Bin Mohd; Hijikuro, Ichiro; Itakura, Shoko; Katakura, Masanori; Todo, Hiroaki; Sugibayashi, Kenji (2020). Enhanced nose-to-brain delivery of tranilast using liquid crystal formulations. Journal of Controlled Release, 325(), 19.
2. Flávia C. Carvalho; Mariana S. Barbi; Victor Hugo V. Sarmento; Leila A. Chiavacci; Flávia M. Netto; Maria P.D. Gremião (2010). Surfactant systems for nasal zidovudine delivery: structural, rheological and mucoadhesive properties. , 62(4),
3. Xiazhong Ren; Darren Svirskis; Raid G. Alany; Sara Zargar-Shoshtari; Zimei Wu (2012). In-situ phase transition from microemulsion to liquid crystal with the potential of prolonged parenteral drug delivery. , 431(1-2), 0–0.
4. Carvalho, Flávia Chiva; Campos, Michel Leandro; Peccinini, Rosângela Gonçalves; Gremião, Maria Palmira Daflon (2013). Nasal administration of liquid crystal precursor mucoadhesive vehicle as an alternative antiretroviral therapy. European Journal of Pharmaceutics and Biopharmaceutics, 84(1), 219–227.

Acknowledgments: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education (2016R1A6A1A03007648). This work was also supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (2022R1C1C1010130).

Figure1. (a) Ternary phase diagram of GMO: co-surfactant(9:1), MCT, and water. red dots = Range where LC is formed, (b) Phase change due to increased co-surfent when samples are prepared according to the fixed W: S: O ratio



Table 1. shows the result of performing an ex vivo experiment. J is Permeation flux and Kp is permeability coefficient.



Figure 2. (a) Permeability change due to surfactant and oil ratio, (b) permeability due to co-surfactant concentration