Self-Nanoemulsifying Drug Delivery System (SNEDDS) for Oral Delivery of Cod Liver Oil

Cod liver oil (CLO) is a food supplement extracted from the cod liver. Cod liver oil has long been used as medicine or as a functional food. Cod liver oil is a potential source of vitamin D, vitamin A, and omega fatty acids (eicosapentaenoic acid/EPA and docosahexaenoic acid/DHA)1. Cod liver oil can prevent heart disease by increasing the elasticity of blood vessels, lowering blood pressure, reducing lipid level, and increasing the HDL level2-4. Cod liver oil can support the treatment of type II diabetes mellitus (T2DM) by increasing insulin sensitivity5. Other studies have shown that CLO has cytotoxic, neuroprotective, hepatoprotective, anti-ulcer, and anti-inflammatory activities. Cod liver oil can also help brain development for children's growth6,7. In oral use, CLO is generally developed as an Emulsionbased delivery system. In the oil in a water emulsion system, CLO is in a dispersed form that is coated or protected by water8,9. The emulsion form of CLO is further modified into a nanoemulsion form10,11. The advantage of the nanoemulsion system is has a small globule size (nano-scale) and increasing its absorption and bioavailability12. However, the study that develops cod liver oil into another form of nanoemulsion system: The self-nanoemulsifying drug delivery system (SNEDDS), has not been carried out. Self-Nanoemulsifying Drug Delivery System (SNEDDS) for Oral Delivery of Cod Liver Oil


INTRODUCTION
Cod liver oil (CLO) is a food supplement extracted from the cod liver. Cod liver oil has long been used as medicine or as a functional food. Cod liver oil is a potential source of vitamin D, vitamin A, and omega fatty acids (eicosapentaenoic acid/EPA and docosahexaenoic acid/DHA) 1 . Cod liver oil can prevent heart disease by increasing the elasticity of blood vessels, lowering blood pressure, reducing lipid level, and increasing the HDL level 2-4 . Cod liver oil can support the treatment of type II diabetes mellitus (T2DM) by increasing insulin sensitivity 5 . Other studies have shown that CLO has cytotoxic, neuroprotective, hepatoprotective, anti-ulcer, and anti-inflammatory activities. Cod liver oil can also help brain development for children's growth 6,7 .
In oral use, CLO is generally developed as an Emulsionbased delivery system. In the oil in a water emulsion system, CLO is in a dispersed form that is coated or protected by water 8, 9 . The emulsion form of CLO is further modified into a nanoemulsion form 10,11 . The advantage of the nanoemulsion system is has a small globule size (nano-scale) and increasing its absorption and bioavailability 12 . However, the study that develops cod liver oil into another form of nanoemulsion system: The self-nanoemulsifying drug delivery system (SNEDDS), has not been carried out.
In this study, CLO was developed in SNEDDS. The SNEDDS is a preconcentrated or anhydrous form of nanoemulsion, a mixture of oils, surfactants, and cosurfactants 13 . This system is expected to self-emulsify quickly in the aqueous stomach system and produces nano globules with a size of

Materials
The materials used in this study were COD (Lancida

Methods
The research was carried out in several stages of the method as shown in Figure 1.

RESULTS AND DISCUSSION
The SNEDDS was known to be one of the nano-based drug delivery systems suitable for the delivery of hydrophilic or lipophilic compounds. The CLO delivery in SNEDDS was expected to increase its dissolution, absorption, and bioavailability. The SNEDDS was prepared by mixing oil, surfactants, and cosurfactants without adding water, so SNEDDS was also known as a preconcentrated or anhydrous form of nanoemulsion 13 .
The SNEDDS would form a nanoemulsion system spontaneously by gastrointestinal (GI) peristaltic.

Miscibility of oil with surfactants and cosurfactants was
important for the effectiveness of SNEDDS formation.
The result showed that CLO has good miscibility property with Cremophor®RH-40 and PEG 400.
Surfactants and cosurfactants in the nanoemulsion were used to form a good and flexible interfacial film and decrease surface tension value to almost zero and support the spontaneous formation of nano globules 25 , as shown in Table II.  Table III. Therefore, the 2 : 1 ratio of surfactant and cosurfactant was used for the following research step.  Table   IV 26 . Therefore, the five formulas of CLO-SNEDDS were continued for further evaluation.   The F2D formula was further evaluated by determining an average of globules size and polydispersity index (PDI) of the nanoemulsion system. The results of globule size analysis using a particle size analyzer showed that CLO-SNEDDS (F2D) was able to form a nanoemulsion system after dilution with a globule size of 125 nm and a PDI value of 0.515. These results followed the globule size requirements for SNEDDS (20-200 nm) and PDI of <0.7 30 .

ACKNOWLEDGMENT
We would like to thank the research Centre of Universitas Islam Bandung for funding this research.

DATA AVAILABILITY
All data are available from the authors.