(T1430-07-39) Improving the Bioavailability of Fenofibrate by Atomic Layer Coating

Purpose: BCS (II) class drugs have poor solubility and high permeability in the body¹. Fenofibrate is a classic example of BCS (II) drug, used to treat high cholesterol and triglyceride (fat-like substances) levels in the blood.² Atomic layer coating (ALC) is an upcoming technology adapted from semiconductor industry, where metal oxides were coated one atomic layer at a time over the API particles.³ ALC coating were proven to improve the processability, alter the hydrophilicity, stability, fine tune the release profile.^4-5 Herein, we report how the ALC coating fenofibrate improves the bioavailability the poorly water-soluble drug in animal model.

Methods: Micronized fenofibrate was used for the study, to investigate the effect of ALC coating. Fenofibrate was ALC coated with zinc oxide and silicon oxide. In-vitro dissolution and solubility studies were performed following office of generic drugs (OGD) guidelines. ¹H NMR, FT-IR, SEM-EDS mapping were performed on the API before and after ALC coating. In-vitro dissolution and solubility studies were performed on API coated with zinc oxide and silicon oxide. In-vivo bioavailability study of the API with and without ALC coating were performed on rodent and larger animal (dog) model. Subacute toxicity study was carried out on uncoated and silicon oxide coated API by oral administration on rodent model.

Results: Fenofibrate has adverse reactivity towards trimethyl aluminum and hence aluminum oxide coating on fenofibrate was not feasible. The precursors used for zinc oxide coating (DEZ/H2O) and silicon oxide coating (SiCl4/H2O) were compatible with the API. After coating, structure of the API was not affected as observed by ¹H NMR and FT-IR. SEM-EDS results shows that the coating was not continuous and hence can influence the dispersibility and hydrophilicity but will not retard the dissolution. ALC coatings shown to improve the in-vitro dissolution of native API without impacting their solubility. Zinc oxide coating helps to improves the flowability of powder and hence improve dispersibility of powder on top of liquid surface, whereas silicon oxide coating on API improves the wettability of the powder. As expected, after ALC coating the powders are very flowable and can be easily processed (can be sieved through ASTM 100 sieve).  ALC coated fenofibrate were loaded into to size 3 capsule (123mg of API) paves the way for formulation with free/reduced number of excipients. Compared to current formulation which has substantial number and amounts of excipients. In-vivo bioavailability study of the API with and without ALC coating were performed on rodent and larger animal (dog) model. Based on AUC, there is a significant increase in bioavailability (~2 times) over the uncoated API. The C_max, values indicated significant increase (~ 3 times) over the uncoated API.  Subacute toxicity study of ALC coated fenofibrate by oral administration were carried out on rodent model. No coating induced toxic effect observed in the coated API.

Conclusion: The current study shows that the ALC technology can be used to improve the bioavailability of BCS (II) compounds. ALC coating improves the dissolution of API by improving the dispersibility and wettability. This dissolution improvement in-vitro tends to correlate well with the bio-availability improvement in-vivo. This study demonstrates the multiple benefits of ALC coating such as improving processibility providing opportunity for drug formulations with less/no excipients, bioavailability improvement in in-vivo.

References: 1) Chavda HV, Patel CN, Anand IS. Biopharmaceutics classification system. Sys Rev Pharm. 2010; 1:62–69.
2) Adkins JC, Faulds D. Micronized fenofibrate: a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia. Drugs. 1997; 54(4):615–633.
3) Tu Van D., Hanh Thuy N., Fei W., Miaojun W., Pravin K. N., Lynne S. T., Surface nanocoating of high drug-loading spray-dried amorphous solid dispersions by atomic layer coating: Excellent physical stability under accelerated storage conditions for two years, International Journal of Pharmaceutics 2022, 620,121747
4) Shrikant S., Balaji Ganapathy., Miaojun W., Fei W., Jamie W., Jonathan F., Shivkumar C., Suraj R., Pravin N. Improving the processability of pharmaceutical powders using atomic layer coating, Powder Technology 2023, 425, 118525
5) Caio H. N. B., Manuel A., Cormac C., Fei W., Kedar S., Suneel R., Shivkumar C., James C., and Elizabeth M. T. Molecular Pharmaceutics 2023 20 (8), 4086-4099.

Acknowledgements: The authors are thankful to TheraIndx, Bengaluru, Karnataka, India for conducting toxicity and pharmacokinetic study on small rodent (Rat) (IAEC no. IAEC/22/2022/253) and Palamour Biosciences, Mahabubnagar, Telangana State, India for pharmacokinetic study on larger animal (Beagle dog) model (IAEC no. SR_PBS_23146).

Figure 1: SEM images of (A) uncoated fenofibrate particles (B) zinc oxide coated fenofibrate particles and (C) silicon oxide coated fenofibrate particles.

Figure 2: (A) In-vitro solubility studies on coated and uncoated fenofibrate (B) Visual observation of uncoated, zinc oxide and silicon oxide coated fenofibrate. (C) In-vitro dissolution studies on coated and uncoated fenofibrate as powders, capsules and as tablets.

Figure 3: Pharmacokinetic study on dogs to understand the improvement in bioavailability between silicon oxide coated and uncoated fenofibrate