The Use of Natural Phospholipids as Pharmaceutical Excipients

Phospholipids are used in many types of formulations such as fat emulsions, mixed micelles, suspensions, and liposomal preparations for any administration route (1-3). Phospholipids are surface-active, comprising a polar headgroup and a lipophilic tail. They are used as emulsifiers, wetting agents, solubilizers, and liposome formers. The phospholipid molecule comprises a glycerol backbone esterified in positions 1 and 2 with fatty acids and in position 3 with phosphate, the latter being further esterified with an alcohol. The most common phospholipid is phosphatidylcholine (PC), which is the main component of lecithin as described in the United States Pharmacopoeia (USP). Phospholipids are essential components of cell membranes, have digestion/metabolic functions (4) as a lipoprotein component, and are a source for the biosynthesis of acetylcholine (in the case of PC) and (essential) fatty acids and energy (5).

Natural phospholipids are isolated from natural sources such as soybean, rape- and sunflower-seed, and animal material (e.g., egg yolk, milk, and krill). These raw materials are produced worldwide at very large scale. The phospholipid compositions of the lecithins are dependent on the raw material sources. In all cases, PC is the main phospholipid component. Higher quality pharmaceutical-grade phospholipids are obtained with excellent inter-batch reproducibility by validated extraction and chromatography procedures using non-toxic solvents (Figure 1).

Figure 1. Flow chart of the isolation process steps of soybean phosphatidylcholine from crude soybean oil.

Control of the raw material quality and use of a validated purification method ensure the quality of the phospholipid excipients. Egg phospholipids, isolated from hen egg yolk with similar methods as for soybean lecithin, play an important role as excipients as well.

Natural phospholipids can be further modified to saturated phospholipids by hydrogenation (6) and use of enzymes to make from soy PC, e.g., soy phosphatidylglycerol (PG) (Figure 2). Besides natural phospholipids, synthetic phospholipids are also being used in pharmaceutical products.

Figure 2. Enzymatic conversion possibilities of phosphatidylcholine (7).

In pharmaceutical products for oral and dermal administration, mainly soybean phospholipids are used. For dermal use, hydrogenated soybean phospholipids are also applied. In parenteral products, natural phospholipids are prevalent in addition to synthetic phospholipids, as described in the FDA’s Inactive Ingredient (excipient) list (Table 1) (8).

Table 1. Examples of parenteral liposome products for human use containing natural phospholipids (in bold).

Egg phospholipids serve as emulsifiers in parenteral nutrition products (e.g., Intralipid®) (10). These emulsions can also be used as carriers for oil-soluble drug substances such as diazepam (Diazemuls®) and propofol (Diprivan®) (11, 12).

Parenteral mixed micellar formulations, comprising soybean phospholipids and cholate salts, are either suitable as solubilizers for poorly water-soluble compounds such as vitamin K or soybean phospholipids intended as APIs for the treatment of liver disorders (13, 14). These products underscore the safe intravenous use of soybean phospholipids.

Considering pulmonary products comprising phospholipids, natural as well as synthetic phospholipids can be used. For instance, natural phospholipids extracted from bovine or calf lung have been used to treat Respiratory Distress Syndrome, a disease in infants characterized by immature lung epithelium (15). The inhalation product for systemic treatment with levodopa (Inbrija®) comprises 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC).

Natural phospholipids are well known to regulatory authorities and described in many pharmacopoeias (16). Regarding the toxicity of phospholipids, the World Health Organization, US FDA, and EU place no limit on the oral intake of lecithin as a food additive (17-19). The safe intravenous use of soybean and egg phospholipids is well documented (20).

In conclusion, natural phospholipids are derived from renewable sources, are produced with ecologically friendly processes, and are available in large scale at relatively low costs. They comply with all requirements from major regulatory authorities and are safe for any administration route. For parenteral application, egg-, soybean-, and hydrogenated soybean phospholipids are used, besides synthetic phospholipids. In oral administration soybean phospholipids prevail, whereas for dermal administration to the skin soybean phospholipids and their hydrogenated versions are popular. Inhalation products contain natural phospholipid extracts and synthetic phospholipids.

References

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FDA, Inactive Ingredient Search for Approved Drug Products. Accessed Aug. 13, 2000, https://www.accessdata.fda.gov/scripts/cder/iig/index.Cfm.

EMA. Myocet liposomal (previously Myocet). Accessed Aug. 13, 2020, https://www.ema.europa.eu/en/medicines/human/EPAR/myocet-liposomal-previously-myocet.

D.F. Driscoll, Pharm. Res. 23 (9) 1959-1969 (2006).

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P. Shah, D. Bhalodia, and P. Shelat, Systematic Reviews in Pharm. 1 (1) 24-32 (2010).

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T.J. Gregory, et al., Am. J. Respir. Crit. Care Med. 155 (4) 1309-1315 (1997).

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WHO, Food Additives Series No. 5., 1974. Accessed Aug. 13, 2020, http://www.inchem.org/documents/jecfa/jecmono/v05je42.htm.

EMA, Commission Regulation (EU) No 231/2012 of 9 March 2012 laying down specifications for food additives listed in Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament and of the Council, 2016. Accessed Aug 13, 2020, https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex:32012R0231.

EMA, European Parliament and Council Directive No 95/2/EC of 20 February 1995 on food additives other than colours and sweeteners, 1996. Accessed Aug 13, 2020, https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A31995L0002.

M. Płaczek, et al., Eur. J. Pharm. Sci. 127, 92-101 (2018).

Correspondence

Dr. Peter van Hoogevest, Phospholipid Research Center Heidelberg, Im Neuenheimer Feld 515, D-69120 Heidelberg, Germany

E Mail: pvanhoogevest@phospholipid-institute.com

Fax: +49 (0) 6221 651 56 65

Figure 1. Flow chart of the isolation process steps of soybean phosphatidylcholine from crude soybean oil.

Figure 2. Enzymatic conversion possibilities of phosphatidylcholine (7).