Development of technology for producing submicron emulsion of propofol using a high-pressure homogenizer

Objectives. Currently, propofol emulsions are widely used in clinical practice due to their rapid action, low toxicity, and ease of administration, including control of anesthetic depth and rapid recovery of the patient following anesthesia. The market offers drugs from both foreign and domestic manufacturers containing imported pharmaceutical substances. The study set out to develop a technology for obtaining a fat emulsion of propofol for parenteral purposes using a high-pressure homogenizer based on pharmaceutical propofol obtained by alkylation and subsequent decarboxylation of 4-hydroxybenzoic acid, as well as to study the physicochemical properties of the obtained submicron emulsions.

Methods. A submicron propofol emulsion was prepared using a high-pressure homogenizer. pH was determined using a pH meter equipped with a combined glass electrode. Particle size and zeta potential of the submicron emulsion were determined on a laser particle analyzer using the dynamic and electrophoretic light-scattering methods, respectively. Quantitative propofol content in the resulting emulsion was determined using high-performance liquid chromatography.

Results. Optimal technological parameters of the high-pressure homogenization process were selected. The method of adding the oil phase directly into the high-pressure homogenizer is shown to entail lower time and energy costs as compared to the homogenization method involving a preliminary stage of obtaining a pre-emulsion. The physicochemical characteristics of the obtained submicron emulsions were subsequently determined to correspond to the characteristics required for the original drug Propofol-Lipuro®.

Conclusions. The proposed technology for obtaining a submicron propofol emulsion for parenteral use is based on dispersion of the aqueous and oil phases using a high-pressure homogenizer. As a result of the study, it was found that adding the oil phase directly into the high-pressure homogenizer at 20 MPa, including further dispersion at 60 MPa for 8 cycles, is optimal for obtaining a submicron propofol emulsion with the required characteristics.

1. Sahinovic M.M., Struys M.M.R.F., Absalom A.R. Clinical Pharmacokinetics and Pharmacodynamics of Propofol. Clin. Pharmacokinet. 2018;57:1539–1558. https://doi.org/10.1007/s40262-018-0672-3

2. Kotani Y., Nakajima Y., Hasegawa T., et al. Propofol Exerts Greater Neuroprotection with Disodium Edetate than without It. J. Cereb. Blood Flow Metab. 2008;28(2):354–366. https:// doi.org/10.1038/sj.jcbfm.9600532

3. Kotani Y., Shimazawa M., Yoshimura S., Iwama T., Hara H. The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neurosci. Ther. 2008;14(2):95–106. https://doi.org/10.1111/j.1527-3458.2008.00043.x

4. Walsh C.T. Propofol: Milk of Amnesia. Cell. 2018;175(1): 10–13. https://doi.org/10.1016/j.cell.2018.08.031

5. Baker M.T., Naguib M., et al. Propofol: The challenges of formulation. Anesthesiology. 2005;103(4):860–876. https://doi.org/10.1097/00000542-200510000-00026

6. Thompson K., Goodale D. The Recent Development of Propofol (DIPRIVAN®). Intensive Care Med. 2000;26(3): 400–404. https://doi.org/10.1007/PL00003783

7. Kam E., Abdul-Latif M.S., McCluskey A. Comparison of Propofol-Lipuro with propofol mixed with lidocaine 10 mg on propofol injection pain. Anaesthesia. 2004;59(12):1167–1169. https://doi.org/10.1111/j.1365-2044.2004.03964.x

8. Sorokina Ye.Yu. Propofol in modern multicomponent general anesthesia. Meditsina neotlozhnykh sostoyanii = Emergency Medicine. 2014;3(58):69–75 (in Russ.).

9. Pramanik C., Kotharkar S.A., Patil P., Gotrane D., More Y.W., Borhade A.S., Chaugule B., Khaladkar T.P., Neelakandan K., Chaudhari A., Kulkarni M.G., Tripathy N.K., Gurjar M.K. Commercial Manufacturing of Propofol: Simplifying the Isolation Process and Control on Related Substances. Org. Process Res. Dev. 2014;18(1):152–156. https://doi.org/10.1021/op400300t

10. Onugwu A.L., Nwagwu C.S., Onugwu O.S., Echezona A.C., et al. Nanotechnology based drug delivery systems for the treatment of anterior segment eye diseases. J. Control. Release. 2023;354:465–488. https://doi.org/10.1016/j.jconrel.2023.01.018

11. Honary S., Zahir F. Effect of Zeta Potential on the Properties of Nano-Drug Delivery Systems – A Review (Part 1). Tropical J. Pharmaceutical Res. 2013;12(2):19. https://doi.org/10.4314/tjpr.v12i2.19

12. Gunar O.V., Dorenskaya A.V. Determination of the size of fat droplets in emulsions for parenteral use. Farmatsiya = Pharmacy. 2022;71(5):11–17 (in Russ.). https://doi.org/10.29296/25419218-2022-05-02

13. Alekseev K.V., Kedik S.A. Farmatsevticheskaya tekhnologiya (Pharmaceutical Technology). Moscow: IFT; 2025. 592 p. (in Russ.).

14. Alison G.F. Top ten considerations in the development of parenteral emulsions. Pharm. Sci. Technol. Today. 1999;2(4): 134–143. https://doi.org/10.1016/S1461-5347(99)00141-8

15. Kumar M., Bishnoi R.S., Shukla A.K., Jain C.P. Techniques for Formulation of Nanoemulsion Drug Delivery System: A Review. Prev. Nutr. Food Sci. 2019;24(3):225–234. https:// doi.org/10.3746/pnf.2019.24.3.225

16. Çinar K. A Review on Nanoemulsion: preparation method and method stability. Tarkya University J. Eng. Sci. 2017;18(1):73–87.

17. Prasetyo B., ShamsuddinA., Azmi N. Preparation and Physical Stability Evaluation of Palm Oil-Based Nanoemulsion as a Drug Delivery System for Propofol. Jurnal Sains Kesihatan Malaysia (Malaysian J. Health Sci.). 2018;16(02):5–13. https://doi.org/10.17576/JSKM-2018-1602-02

18. Rooimans T., Damen M., Markesteijn C.M.A., Schuurmans C.C.L., de Zoete N.H.C., van Hasselt P.M., Hennink W.E., van Nostrum C.F., Hermes M., Besseling R., Vromans H. Development of a compounded propofol nanoemulsion using multiple non-invasive process analytical technologies. Int. J. Pharm. 2023;640:122960. https://doi.org/10.1016/j.ijpharm.2023.122960

19. Prasetyo B., Azmi N., Shamsuddin A. In vivo characterization of less painful propofol nanoemulsion using palm oil for intravenous drug delivery. Int. J. Appl. Pharm. 2019;11(4): 98–102. https://doi.org/10.22159/ijap.2019v11i4.33039