Preparation and evaluation of novel mixed micelles as nanocarriers for intravenous delivery of propofol
© Li et al; licensee Springer. 2011
Received: 8 November 2010
Accepted: 31 March 2011
Published: 31 March 2011
Novel mixed polymeric micelles formed from biocompatible polymers, poly(ethylene glycol)-poly(lactide) (mPEG-PLA) and polyoxyethylene-660-12-hydroxy stearate (Solutol HS15), were fabricated and used as a nanocarrier for solubilizing poorly soluble anesthetic drug propofol. The solubilization of propofol by the mixed micelles was more efficient than those made of mPEG-PLA alone. Micelles with the optimized composition of mPEG-PLA/Solutol HS15/propofol = 10/1/5 by weight had particle size of about 101 nm with narrow distribution (polydispersity index of about 0.12). Stability analysis of the mixed micelles in bovine serum albumin (BSA) solution indicated that the diblock copolymer mPEG efficiently protected the BSA adsorption on the mixed micelles because the hydrophobic groups of the copolymer were efficiently screened by mPEG, and propofol-loaded mixed micelles were stable upon storage for at least 6 months. The content of free propofol in the aqueous phase for mixed micelles was lower by 74% than that for the commercial lipid emulsion. No significant differences in times to unconsciousness and recovery of righting reflex were observed between mixed micelles and commercial lipid formulation. The pharmacological effect may serve as pharmaceutical nanocarriers with improved solubilization capacity for poorly soluble drugs.
Propofol, chemically named 2,6-diisopropylphenol, is a highly effective and rapid intravenous anesthetics, which has gained increasing popularity in anesthesia in clinic. Its greatest advantage is the rapid recovery, even after long periods of anesthesia. A particularly low incidence of postoperative nausea and vomiting was also observed [1, 2]. However, it also has some drawbacks such as poor water miscibility (150 μg/L)  and high lipophilicity (logP = 4.16) . As vehicles for clinical delivery of anesthetics should be devoid of sedative and anesthetic properties, as well as toxic side effects, nearly all small-molecular weight organic solvents into which propofol is freely miscible are not useful. Therefore, propofol was initially formulated as a 1% solution in 16% Cremophor EL, which has been reported to induce undesirable side effects, such as the high occurrence of pain on injection and the risk of anaphylactic reactions associated to Cremophor EL. In view of the clinical importance of propofol, the alternative formulations such as oil/water emulsion consisting of soya bean oil, glycerol, and egg phosphatide (Diprivan®, Zeneca, UK) , microemulsions , inclusion complex , and polymeric micelles [7, 8], have been developed to improve its solubility. Unfortunately, lipid-based emulsions suffer from other limitations including poor physical stability and the potential for embolism. Strictly aseptic techniques must be maintained when handling these formulations since they do not contain antimicrobial preservatives, and the vehicle can support rapid growth of microorganisms [9, 10]. Among other particulate vehicles, polymeric micelles have presented their great potential in solubilization of poorly water-soluble drugs in recent years [11–14]. Generally, block copolymers with concentration above the critical micellization concentration (CMC) self-assemble into spherical polymeric micelles with a core-shell structure in water: the hydrophobic segments aggregate to form an inner core being able to accommodate hydrophobic drugs with improved solubility by hydrophobic interactions; the hydrophilic shell consists of a brush-like protective corona that stabilizes the micelles in aqueous solution [15–17]. Polymeric micelles as novel drug vehicles present numerous advantages, such as reduced side effects of drugs, selective targeting, stable storage, and stability toward dilution [17, 18]. Furthermore, polymeric micelles possess a nanoscaled size with a narrow distribution. They can protect drugs against oxidation in vitro and premature degradation in vivo owing to their core-shell architecture [19, 20]. More importantly, polymeric micelles are fabricated according to the physicochemical properties of drugs and the compatibility between the core of micelles and drug molecules [14, 21]. Unfavorably, propofol-loaded polymeric micelles formed from poly(N-vinyl-2-pyrrolidone)-block-poly(d,l-lactide) (PVP-PLA) copolymers [7, 8], the drug loading content (LC) was extremely low (7 to 12%). Therefore, there has been an urgent quest to develop an ideal polymeric micelles formulation that can solubilize propofol efficiently and solve some of the aforementioned problems.
This study presented a newly mixed micelle structure of methoxy poly(ethylene glycol)-b-poly(d,l-lactide) (mPEG-PLA) diblock copolymers and Solutol HS 15, which was expected to manifest increased drug loading efficiency, superior to those of the individual components, and at least maintain the efficacy of propofol. Solutol HS 15, the main component of which is the polyethylene glycol 660 ester of 12-hydroxy stearic acid, is a low molecular weight surfactant and recommended as non-ionic solubilizing agent to be added to injection solutions . Its relatively bulky lipophilic portion might allow it for better drug solubilization. This micellar structure involved not only the modification of particles to hide the inner structure to prevent recognition by the physiological system, but also a new means of preparing micelles with higher drug LC from a copolymer with a low molecular weight surfactant. Therefore, the micelle preparation, propofol solubilization, and in vitro micelle properties were investigated by the size measurement, drug LC, encapsulation efficiency (EE), physical stability, and in vitro drug release. The in vivo pharmacological effect of propofol-loaded mixed micelles was also evaluated.
Materials and methods
Propofol was purchased from Zhongke Taidou Chemical Co., Ltd. (Shandong, China). mPEG5000-PLA4800 copolymers were synthesized in our laboratory as previously described . Solutol HS15 was obtained from Yunhong Chemical Co., Ltd (Shanghai, China). The commercial lipid emulsion (CLE) injection for propofol (1%, w/v) was provided by Guorui Pharmaceutical Co., Ltd. (Sichuan, China). All other reagents were of analytical grade, except those for HPLC assay which were of HPLC grade.
Sprague-Dawley (SD) rats weighing 200 ± 20 g were obtained from Animals Center of Peking University Health Science Center. All animals were provided with standard food and water ad libitum and were exposed to alternating 12-h periods of light and darkness. Temperature and relative humidity were maintained at 25°C and 50%, respectively. All care and handling of animals were performed with the approval of Institutional Authority for Laboratory Animal Care of Peking University.
Determination of critical micellization concentration
The CMC was determined by fluorescence spectroscopy using pyrene (Fluka, > 99%, St. Louis, USA) as a hydrophobic probe as previously reported . The fluorescence spectra of pyrene were measured at varying mixed micelle concentrations using a Shimadzu RF-5301 PC fluorescence spectrometer (Kyoto, Japan) at 25°C. The excitation wavelength was adjusted to 392 nm, and the detection of fluorescence was performed at 333 and 335 nm. CMC was measured from the onset of a rise in the intensity ratio of peak at 335 nm to peak at 333 nm in the fluorescence spectra of pyrene plotted versus the logarithm of polymer concentration.
Preparation of mixed micelles
The drug-free mixed micelles were prepared by rotary evaporation method . In brief, a methanol solution of mPEG-PLA and Solutol HS15 with different molar ratios was evaporated under vacuum at 60°C to form a homogeneous film. The resulting film was dispersed in 10 mL of water at 60°C and then vortexed for 3 min. Then the mixture was filtered through a 0.45-μm filter (Millex-GV, Millipore, USA) to obtain a clear and homogeneous micelle solution. The propofol-loaded mixed micelles were prepared by mixing propofol and the prepared drug-free micelle solution under magnetic agitation at room temperature. Then the resultant mixture was incubated at 4°C for 30 min and filtered. The filtrate was filled into ampoules and sealed under nitrogen.
Particle size measurement
A certain volume of micelle solution was diluted with water to a definite volume in a flask and shaken gently to mix thoroughly. Samples were then passed through 0.22-μm pore-size filter before size measurement to remove dust particles. The average particle size and size distribution of micelles were determined by dynamic light scattering (DLS) (Zetasizer ZEN 3600, Malvern, UK) with a scattering angle of 90° at 25°C. The results were the mean values of three experiments for the same sample.
Determination of drug loading content and encapsulation efficiency
In vitro release of propofol from micelles
One milliliter of micelles solution with known propofol content was placed into a dialysis bag with molecular weight cutoff of 3 kD. The dialysis bag was immersed into a flask containing 30 mL of release medium (phosphate buffer saline (PBS), pH 7.4) containing 30% (v/v) alcohol (sink condition) which was kept in a constant temperature shaking water bath at 37°C and 100 rpm. At predetermined time intervals, aliquots (1 mL) of the release medium was taken and replaced by fresh medium. The content of propofol in the medium was measured by HPLC method as described above. The cumulative release percentage of propofol was calculated. The CLE was also tested as control.
Stability of mixed micelles in bovine serum albumin solution
The stability of mixed micelles in bovine serum albumin (BSA) solution was assessed from the change of particle size of micelles and the micellar propofol upon incubation of the mixed micelles with 0.2% BSA solution [24, 25]. The mixture was incubated under shaking at the speed of 100 rpm at 37°C for 24 h and determined the particle size at time interval, defined as d i. The average diameter of micelles before BSA treatment, d 0, was also measured. The ratio of particle sizes was calculated as d i/d 0. In addition, the determination of the EE was performed using the same method described above.
Stability of mixed micelles under storage condition
The physical stability of mixed micelles under storage conditions was also evaluated. Freshly prepared drug-loaded mixed micelles were transferred into glass vials and then stored at 25°C for 6 months. The stability of micelles was monitored by the time-dependent changes in the physical characteristics, like drug precipitation, changes in micelle size, and drug LC during the storage period.
Male SD rats weighing 200 ± 20 g were used for this research. All animals were housed with free access standard food and tap water, and exposed to alternating 12 h periods of light and darkness. Temperature and relative humidity were maintained at 25°C and 50%, respectively. After an acclimatization period of 2 days, the rats were fasted for 12 h but allowed free access to water prior to the experiments. Eighteen rats were randomly divided using a random number generator into two groups (n = 9). The rats in each group received their respective formulations (mixed micelles sterilized by filtration through a 200-nm pore filter or CLE) via the caudal vein at a single dose of 10 mg/kg. The end of injection was taken as time zero (t = 0). After each administration, the time to loss of righting reflex was recorded for each animal. Rats were maintained in dorsal or lateral recumbency during evaluation, and the time of righting reflex return was recorded.
All data were expressed as mean standard deviation (SD) unless particularly outlined. The statistical significance of differences among more than two groups was determined by one-way ANOVA by the software SPSS 13.0. A value of p < 0.05 was considered to be significant.
Results and discussion
Effect of Solutol HS15 content on critical micelle concentration of PEG5000-PLA4800
Effect of Solutol HS15 content on the properties of the copolymer and polymeric micelle at 25°C.
Mole ratio of mPEG-PLA to Solutol HS 15
On the other hand, it should be noted that the CMC of mixed micelles decreased with increase of mPEG-PLA content. Clearly, a major problem encountered with Solutol HS15 plain micelles was their relatively high critical micelle concentration (Table 1), which resulted in the dissociation of micelles into monomers upon dilution. Due to this instability, additional stabilization was required by addition of mPEG-PLA. It was found that the CMC of the mixed system composed of mPEG-PLA and Solutol HS 15 at molar ratio of 1:1 was still lower (11.5 mg/L, expressed with the content of mPEG-PLA), which pointed on their high stability to maintain the integrity even upon strong dilution in vivo due to the fact that the content of mPEG-PLA in the prepared mixed micelles was almost 6 mg/mL.
Optimization of micelle composition and characterization of mixed micelles
The effect of molar ratio of Solutol HS15 to mPEG-PLA on properties of micelles.
Molar ratio of Solutol HS15 to mPEG-PLA
Drug-free micelles size (nm)
88.1 ± 4.1
83.3 ± 3.5
80.2 ± 3.6
78.3 ± 5.1
0.16 ± 0.03
0.17 ± 0.04
0.19 ± 0.07
0.16 ± 0.06
Drug-loaded micelles size (nm)
119.9 ± 5.5
117.1 ± 6.1
101.0 ± 3.8
94.4 ± 6.4
0.17 ± 0.11
0.19 ± 0.04
0.12 ± 0.09
0.18 ± 0.08
21.1 ± 3.2
26.5 ± 1.5*
32.4 ± 1.3**
36.0 ± 2.4***
Determination of the content of free propofol in micelle solutions
The stability of mixed micelle at room temperature (25°C).
Particle size (nm)
101.3 ± 5.3
103.6 ± 6.2
0.16 ± 0.06
0.18 ± 0.05
Concentration of free propofol (μg/mL)
5.28 ± 0.38
5.19 ± 0.52
35.3 ± 2.8
33.7 ± 2.5
Stability of mixed micelles
Additionally, the micellar propofol was also determined to further elucidate the effect of dilution on stability of mixed micelles. The results showed no significant change in EE of mixed micelles for 10- and 100-fold dilution (Figure 4), whereas the mixed micelles presented dramatic change in EE under 400-fold dilution, suggesting that the mixed micelles were stable in the presence of BSA at lower dilution extent, and part of the micelles began to dissociate when they were diluted near to critical micellization concentration. Nevertheless, the concentration of free propofol in aqueous phase was only in the range 1.2 to 5.0 μg/mL, which was considerably lower compared to the CLE, due to the huge dilution extent.
The storage stability of mixed micelles was also tested at 25°C for 6 months. As shown in Table 3, propofol-loaded mixed micelle formulations did not show any noticeable change in the particle size and PDI, and no precipitation of drug was found during this period. In addition, the LC of mixed micelles had a loss of only 2.4%, probably due to the partial decomposition of propofol. These indicated that the drug-loaded micelles were physically stable at room temperature for at least 6 months. The long-term stability of propofol-loaded mixed micelles is currently being evaluated.
In vitro release of propofol from micelles
The propofol release profile from mPEG-PLA/Solutol HS15 mixed micelles was presented in Figure 5. The comparison of the profiles of propofol release from the micelles and the aqueous solution showed that the entrapment of propofol in the nanoparticles could significantly retard its in vitro release [11, 18, 23]. In addition, it was observed that the propofol release from mPEG-PLA/Solutol HS15 mixed micelles started with an initial burst, followed by a very slow release phase. This release behavior could be explained through the geometry of propofol location in the micelles and reflected the propofol incorporation stability. The initial burst happened within the first 4 h, especially within the first 2 h, was mainly attributed to the drug located in the hydrophilic corona or shell of micelles, and could proceed via both the hydration of the interfacial drug molecules and their passive diffusion. Thereafter, the slower propofol release resulted from that localized in the inner core of micelles.
In addition, the cumulative release percentage, about 75.5%, of propofol from mixed micelles within 48 h was about 2-fold greater than that (about 38.3%) from commercial formulation (CLE), and the accumulative release of mixed micelles was significantly higher than that of CLE at all the time points. These might be accounted for the larger globule size of CLE induced relatively slower diffusion of the drug from inner phase and then slower release. Nevertheless, the release rate of mixed micelles was faster than that of CLE before the first 12 h, the release rate of the two formulations was comparable thereafter. Overall, quick release rate for mixed micelles might produce a favorable pharmacological effect for drugs, especially for propofol, which exhibits rapid sleep and recovery.
Mixed micelles consisted of mPEG-PLA and Solutol HS15 were designed and provided a more efficient solubilization of the poorly soluble drug, propofol, as compared with plain micelles made of mPEG-PLA alone. Stability studies showed that the mixed micelles were stable in the presence of BSA at different dilution extent and there was no effect of dilution on the stability of micelles, which is very important for a drug delivery system because one of the important differences between the in vitro and in vivo conditions is the dilution effect under in vivo administration. In addition, the drug-loaded mixed micelles were physically stable at room temperature for at least 6 months. As anticipated, the free propofol present in the aqueous phase was significantly reduced by mixed micelles. The pharmacological effect of mixed micelles was proved to be comparable to that of the commercial formulation. This study not only provided an idea for preparing a novel drug carrier from two amphiphilic materials, but also overcame some drawbacks on propofol injection.
bovine serum albumin
commercial lipid emulsion
critical micellization concentration
dynamic light scattering
phosphate buffer saline
mean standard deviation.
We would like to acknowledge the support of this work by the National Development of Significant New Drugs (New Preparation and New Technology, 2009zx09310-001) and the National Basic Research Program of China (973 program, 2009CB930300).
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