Faisal W., O'Driscoll C. M. and Griffin B. T.1 Solubility and stability of lycopene in lipid-based formulations. Faisal W., O'Driscoll C. M. and Griffin B. T.1 1Pharmaceutics, School of Pharmacy, University College Cork, Ireland w.faisal@mars.ucc.ie The solubility of lycopene in LCT SMEDDS was higher (261.6± 8.0µg/ml) than in MCT SMEDDS (237±7.3µg/ml). Introduction Lycopene, a natural antioxidant, has displayed considerable potential as a chemoprevenatative agent, with epidemiological studies supporting a 25-30% reduction in prostate cancer risk[1]. Uptake of lycopene from dietary food stuffs however is highly variable and poorly understood. Lycopene is highly lipophilic carotenoid (clog P = 17.6) and displays low aqueous soluble. The oral bioavailability of highly lipophilic compounds is known to be enhanced by lipid based formulations[2]. A lipid based formultion approach may serve to enhance solubilisation within the gastrointestinal contents, promote uptake within enterocytes and stimulate intetsinal lymphatic transport. Objectives The objective of the work is to study the solubility and stability of lycopene in a range of lipid vehicles including self micro-emulsifying drug delivery systems (SMEDDS). Figure 2: UV Spectrophotometer scan and image of lycopene stability in different lipid vehicles at time zero. Figure 4: UV Spectrophotometric scan and image of lycopene stability in LCT and MCT SMEDDS at time zero. Methods Lycopene solubility in oleic acid, triolein, olive oil, soybean oil and miglyol oil was determined by UV analysis. HPLC equipped with a C30 column was used to monitor the degree of lycopene isomerisation. The identification of lycopene isomers is based on the retention time, spectral data, λmax and Q-value. Solubility and stability of lycopene in two SMEDDS (Olive oil; Tween 85; Cremophor RH (40; 40; 20) and Miglyol oil; Tween85; Cremophor RH (40; 40; 20)) were studied. All experiments were performed in absence of light and at ambient temperature. Figure 5: UV Spectrophotometric scan and image of lycopene stability in LCT and MCT SMEDDS after 7days. Results For MCT SMEDDS significant degradation occurred within 72 hours and was complete after 9 days. LCT SMEDDS were more stable then MCT SMEDDS (Fig.4 and Fig. 5). Formation of a SMEDDS using LCT increased the solubility relative to the pure oil and reduced the degree of isomerisation of lycopene (Table 3). Figure 3: UV Spectrophotometric scan and images of lycopene stability in different lipid vehicles after 8 days. Initially, in all lipids studied >90% of lycopene was present as the all-trans isomer (Fig.2). In oleic acid, significant degradation occurred within 24 hours and was complete by 3 days. Degradation of lycopene in Miglyol and triolein was also observed with complete loss of lycopene within 8 days (Fig. 3). Table 2: Stability of lycopene in different oils over 3 weeks at 20±2°C and in absence of light. . Table 3: Stability data of lycopene in LCT and MCT SMEDDS over 3 weeks. Oil % remaining % of isomers (7Z,9Z) (7Z,9Z, 7`Z,9`Z) (9Z,9`Z) (15Z) (13Z) (5Z,5`Z) (9Z) (All-E) (5Z) Olive 100 % 0.26 1.02 0.2 0.34 3.24 0.14 94.81 Triolein 0.68 0.54 0.10 2.33 95.10 0.99 Oleic 0.39 0.38 0.24 0.37 3.15 93.95 1.52 Miglyol 0.85 0.73 0.35 0.44 3.29 0.12 94.23 Soybean 0.33 0.64 0.15 2.76 96.02 1week 67.58 % 0.9 0.16 0.22 1.22 11.69 0.25 65.31 20.27 9.66 % 2.69 16.57 2.01 12.35 0.41 29.85 36.13 Degraded 66.5 % 1.30 1.21 11.74 0.211 63.70 21.25 21days 55.48 % 1.35 0.17 1.17 12.15 0.82 0.89 39.33 43.77 53.55 % 1.72 0.48 1.26 12.56 .28 43.99 39.48 LCT SMEDDS Time % remaining % of isomers (7Z,9Z) (7Z,9Z, 7`Z,9`Z) (9Z,9`Z) (15Z) (13Z) (5Z,5`Z) (9Z) (All-E) (5Z) Fresh 100 % 0.64 0.12 0.72 0.36 2.27 0.17 0.31 95.42 1week 69.86 % 1.24 0.46 0.59 4.86 0.32 89.95 2.59 3week 56.97 3.24 1.31 0.53 1.62 10.63 0.69 0.3 72.99 8.69 MCT SMEDDS 0.94 0.39 1.2 0.42 2.76 0.22 93.77 20.33% 4.56 9.41 1.29 5.28 78.98 0.49 9days Degraded Figure 1: Isomer profile of standard lycopene dissolved in ethyl acetate evaluated on a C30 HPLC column Pure Lycopene standard is composed of 95% all-trans lycopene and 5% Cis isomers. The trans form is considered the most thermodynamically stable isomer (Fig. 1). Conclusion The type of lipid excipients influences the solubility and stability of lycopene. Although MCT displayed higher lycopene solubility, in general, lycopene displayed greater stability in LCT. SMEDDS of LCT display have higher lycopene solubility and less degradation of lycopene compared to MCT. SMEDDS have potential to produce stable lycopene formulations for oral administration. Table 1: Solubility of lycopene in a range of lipid vehicles at 20±2°C and in absence of light. Lipid vehicle Olive oil Triolein Oleic acid Miglyol oil Soybean oil Solubility µg/ml 211.6±5 145±1 119.4±5.7 264.8±17.4 197 Degradation in the LCT lipids, Olive oil and Soybean oil was less pronounced (Table 2). On storage, the proportion of trans isomer decreased and the cis increased in all lipid vehicles. The solubility of lycopene was highest in the Miglyol (a medium chain triglyceride (MCT)), followed in rank order by olive oil (long chain triglyceride LCT), soybean oil (LCT), triolein (LCT), and oleic acid (long chain fatty acid) Table 1. References Giovannucci E. J. of Nutrition 135: 2030S-2031S, 2005. O'Driscoll, CM, & Griffin, B.T. Adv. Drug Del. Reviews. 60:617-624, 2008.